N-aryl diazaspiracyclic compounds and methods of preparation and use thereof

ABSTRACT

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are N-aryl diazaspirocyclic compounds, bridged analogs of N-heteroaryl diazaspirocyclic compounds, or prodrugs or metabolites of these compounds. The aryl group can be a five- or six-membered heterocyclic ring (heteroaryl). The compounds and compositions can be used to treat and/or prevent a wide variety of conditions or disorders, particularly those disorders characterized by dysfunction of nicotinic cholinergic neurotransmission, including disorders involving neuromodulation of neurotransmitter release, such as dopamine release. CNS disorders, which are characterized by an alteration in normal neurotransmitter release, are another example of disorders that can be treated and/or prevented. The compounds and compositions can also be used to alleviate pain. The compounds can: (i) alter the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) when employed in effective amounts, not result in appreciable adverse side effects (e.g., side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle).

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 11/173,944,filed on Jul. 1, 2005 now U.S. Pat. No. 7,291,731, which is a divisionof application Ser. No. 10/607,930, filed on Jun. 27, 2003 now U.S. Pat.No. 6,956,042, which itself claimed priority to Provisional ApplicationNo. 60/394,337, filed Jul. 5, 2002, the contents of each of which arehereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositionsincorporating compounds capable of affecting nicotinic cholinergicreceptors, for example, as modulators of specific nicotinic receptorsubtypes. The present invention also relates to methods for treating awide variety of conditions and disorders, particularly those associatedwith dysfunction of the central and autonomic nervous systems.

BACKGROUND OF THE INVENTION

Nicotine exhibits a variety of pharmacological effects (Pullan et al.,N. Engl. J. Med. 330:811-815 (1994)), some of which are due toneurotransmitter release (See, for example, Sjak-shie et al., Brain Res.624:295 (1993), where neuroprotective effects of nicotine are proposed).For example, acetylcholine, dopamine, norepinephrine, serotonin andglutamate are released by neurons upon administration of nicotine(Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et al., J.Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313 (1991),Vizi, Br. J. Pharmacol. 47:765 (1973), Hall et al., Biochem. Pharmacol.21:1829 (1972), Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91(1977), and Toth et al., Neurochem Res. 17:265 (1992)). Confirmatoryreports and additional recent studies show that nicotine administrationmodulates glutamate, nitric oxide, GABA, takykinins, cytokines andpeptides in the central nervous system (CNS) (reviewed in Brioni et al.,Adv. Pharmacol. 37:153 (1997)). Nicotine also reportedly potentiates thepharmacological behavior of certain pharmaceutical compositions used totreat certain disorders. See, for example, Sanberg et al., Pharmacol.Biochem. & Behavior 46:303 (1993); Harsing et al., J. Neurochem. 59:48(1993) and Hughes, Proceedings from Intl. Symp. Nic. S40 (1994). Variousadditional beneficial pharmacological effects of nicotine have beenproposed. See, for example, Decina et al., Biol. Psychiatry 28:502(1990); Wagner et al., Pharmacopsychiatry 21:301 (1988); Pomerleau etal., Addictive Behaviors 9:265 (1984); Onaivi et al., Life Sci.54(3):193 (1994); Tripathi et al., J. Pharmacol. Exp. Ther. 221:91(1982)and Hamon, Trends in Pharmacol. Res. 15:36 (1994).

In addition to nicotine itself, a variety of nicotinic compounds arepurportedly useful for treating a wide variety of conditions anddisorders. See, for example, Williams et al., Drug News Perspec.7(4):205 (1994); Arneric et al., CNS Drug Rev. 1(1): 1 (1995); Arnericet al., Exp. Opin. Invest. Drugs 5(1):79 (1996); Bencherif et al., J.Pharmacol. Exp. Ther. 279:1413 (1996); Lippiello et al., J. Pharmacol.Exp. Ther. 279:1422 (1996); Damaj et al., J. Pharmacol. Exp. Ther.291:390 (1999); Chiari et al., Anesthesiology 91:1447 (1999);Lavand'homme and Eisenbach, Anesthesiology 91:1455 (1999); Holladay etal., J. Med. Chem. 40(28): 4169 (1997); Bannon et al., Science 279: 77(1998); PCT WO 94/08992, PCT WO 96/31475, PCT WO 96/40682, and U.S. Pat.Nos. 5,583,140 to Bencherif et al., 5,597,919 to Dull et al., 5,604,231to Smith et al. and 5,852,041 to Cosford et al.

Nicotine and various nicotinic compounds are reportedly useful fortreating a wide variety of CNS disorders. See, for example, U.S. Pat.Nos. 5,1871,166 to Kikuchi et al., 5,672,601 to Cignarella, PCT WO99/21834 and PCT WO 97/40049, UK Patent Application GB 2295387 andEuropean Patent Application 297,858. CNS disorders are a type ofneurological disorder. They can be drug induced; attributed to geneticpredisposition, infection or trauma; or of unknown etiology. CNSdisorders include neuropsychiatric disorders, neurological diseases andmental illnesses, and include neurodegenerative diseases, behavioraldisorders, cognitive disorders and cognitive affective disorders. Thereare several CNS disorders whose clinical manifestations have beenattributed to CNS dysfunction (i.e., disorders resulting frominappropriate levels of neurotransmitter release, inappropriateproperties of neurotransmitter receptors, and/or inappropriateinteraction between neurotransmitters and neurotransmitter receptors).Several CNS disorders can be attributed to a deficiency of choline,dopamine, norepinephrine and/or serotonin.

Relatively common CNS disorders include pre-senile dementia (early-onsetAlzheimer's disease), senile dementia (dementia of the Alzheimer'stype), micro-infarct dementia, AIDS-related dementia, Creutzfeld-Jakobdisease, Pick's disease, Parkinsonism including Parkinson's disease,progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia,hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia,schizophrenia, depression, obsessive-compulsive disorders and Tourette'ssyndrome.

A limitation of some nicotinic compounds is that they are associatedwith various undesirable side effects, for example, by stimulatingmuscle and ganglionic receptors. It would be desirable to havecompounds, compositions and methods for preventing and/or treatingvarious conditions or disorders (e.g., CNS disorders), includingalleviating the symptoms of these disorders, where the compounds exhibitnicotinic pharmacology with a beneficial effect (e.g., upon thefunctioning of the CNS), but without significant associated sideeffects. It would further be highly desirable to provide compounds,compositions and methods that affect CNS function without significantlyaffecting those receptor subtypes which have the potential to induceundesirable side effects (e.g., appreciable activity at cardiovascularand skeletal muscle sites). The present invention provides suchcompounds, compositions and methods.

SUMMARY OF THE INVENTION

Compounds, pharmaceutical compositions including the compounds, andmethods of preparation and use thereof are disclosed. The compounds areN-aryl diazaspirocyclic compounds, bridged analogs of N-heteroaryldiazaspirocyclic compounds, or prodrugs or metabolites of thesecompounds. The aryl group can be a five- or six-membered heterocyclicring (heteroaryl). Examples of the N-aryl diazaspiocyclic compoundsinclude 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane and1-(3-pyridyl)-1,7-diazaspiro[4.4]nonane. Examples of bridged analogs ofN-heteroaryl diazaspirocyclic compounds include1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine].

The compounds and compositions can be used to treat and/or prevent awide variety of conditions or disorders, particularly those disorderscharacterized by dysfunction of nicotinic cholinergic neurotransmission,including disorders involving neuromodulation of neurotransmitterrelease, such as dopamine release. CNS disorders, which arecharacterized by an alteration in normal neurotransmitter release, areanother example of disorders that can be treated and/or prevented. Thecompounds and compositions can also be used to alleviate pain. Themethods involve administering to a subject an effective amount of anN-aryl diazaspirocyclic compound, bridged analog of an N-heteroaryldiazaspirocyclic compound, or prodrug or metabolite thereof to alleviatethe particular disorder.

The pharmaceutical compositions include an effective amount of thecompounds described herein. When employed in effective amounts, thecompounds can interact with relevant nicotinic receptor sites of asubject and act as a therapeutic agent to prevent and/or treat a widevariety of conditions and disorders, particularly those disorderscharacterized by an alteration in normal neurotransmitter release. Thepharmaceutical compositions provide therapeutic benefit to individualssuffering from such disorders and exhibiting clinical manifestations ofsuch disorders. When employed in effective amounts, the compounds havethe potential to: (i) exhibit nicotinic pharmacology and affect relevantnicotinic receptors sites (e.g., bind to nicotinic acetylcholinereceptors and modulate their function, and/or (ii) modulateneurotransmitter secretion and thus prevent and suppress the symptomsassociated with those diseases. In addition, the compounds can: (i)alter the number of nicotinic cholinergic receptors of the brain of thepatient, (ii) exhibit neuroprotective effects and (iii) when employed ineffective amounts, not result in appreciable adverse side effects (e.g.,side effects such as significant increases in blood pressure and heartrate, significant negative effects upon the gastro-intestinal tract, andsignificant effects upon skeletal muscle). The pharmaceuticalcompositions are believed to be safe and effective with regards toprevention and treatment of a wide variety of conditions and disorders.

The foregoing and other aspects of the present invention are explainedin detail in the detailed description and examples set forth below.

DETAILED DESCRIPTION OF THE INVENTION

Compounds, pharmaceutical compositions including the compounds, andmethods of preparation and use thereof are disclosed.

The following definitions will be useful in understanding the metes andbounds of the invention as described herein.

As used herein, “alkyl” refers to straight chain or branched alkylradicals including C₁-C₈, preferably C₁-C₅, such as methyl, ethyl, orisopropyl; “substituted alkyl” refers to alkyl radicals further bearingone or more substituent groups such as hydroxy, alkoxy, aryloxy,mercapto, aryl, heterocyclo, halo, amino, carboxyl, carbamyl, cyano, andthe like; “alkenyl” refers to straight chain or branched hydrocarbonradicals including C₁-C₈, preferably C₁-C₅ and having at least onecarbon-carbon double bond; “substituted alkenyl” refers to alkenylradicals further bearing one or more substituent groups as definedabove; “cycloalkyl” refers to saturated or unsaturated, non-aromatic,cyclic ring-containing radicals containing three to eight carbon atoms,preferably three to six carbon atoms; “substituted cycloalkyl” refers tocycloalkyl radicals further bearing one or more substituent groups asdefined above; “aryl” refers to aromatic radicals having six to tencarbon atoms; “substituted aryl” refers to aryl radicals further bearingone or more substituent groups as defined above; “alkylaryl” refers toalkyl-substituted aryl radicals; “substituted alkylaryl” refers toalkylaryl radicals further bearing one or more substituent groups asdefined above; “arylalkyl” refers to aryl-substituted alkyl radicals;“substituted arylalkyl” refers to arylalkyl radicals further bearing oneor more substituent groups as defined above; “heterocyclyl” refers tosaturated or unsaturated cyclic radicals containing one or moreheteroatoms (e.g., O, N, S) as part of the ring structure and having twoto seven carbon atoms in the ring; “substituted heterocyclyl” refers toheterocyclyl radicals further bearing one or more substituent groups asdefined above.

I. Compounds

The compounds are N-aryl diazaspirocyclic compounds, bridged analogs ofN-heteroaryl diazaspirocyclic compounds, prodrugs or metabolites ofthese compounds, and pharmaceutically acceptable salts thereof.

The compounds can bind to, and modulate nicotinic acetylcholinereceptors in the patient's brain in the cortex, hippocampus, thalamus,basal ganglia, and spinal cord. When so bound, the compounds expressnicotinic pharmacology and, in particular, modulate the release ofvarious neurotransmitters including dopamine, other catecholamines suchas norepinephrine, serotonin, acetylcholine, GABA, glutamate,neuropeptides, nitric oxide, cytokines and other neurotransmitters andneuromediators.

Receptor binding constants provide a measure of the ability of thecompound to bind to half of the relevant receptor sites of certain braincells of the patient. See, for example, Cheng et al., Biochem.Pharmacol. 22:3099 (1973). The receptor binding constants of thecompounds described herein generally exceed about 0.1 nM, often exceedabout 1 nM, and frequently exceed about 10 nM, and are generally lessthan about 100 μM, often less than about 10 μM and frequently less thanabout 5 μM. Preferred compounds generally have receptor bindingconstants less than about 2.5 μM, sometimes are less than about 1 μM,and can be less than about 100 nM.

The compounds described herein can demonstrate a nicotinic function byeffectively activating neurotransmitter secretion from nerve endingpreparations (i.e., synaptosomes). As such, these compounds can activaterelevant neurons to release or secrete acetylcholine, dopamine, andother neurotransmitters. Generally, typical compounds activate dopaminesecretion in amounts of at least one third, typically at least about 10times less, frequently at least about 100 times less, and sometimes atleast about 1,000 times less than those required for activation ofmuscle-type nicotinic receptors. Certain compounds elicit dopaminesecretion in an amount which is comparable to that elicited by an equalmolar amount of (S)-(−)-nicotine.

Preferably, the compounds can cross the blood-brain barrier, and thusenter the central nervous system of the patient. Log P values provide ameasure of the ability of a compound to pass across a diffusion barrier,such as a biological membrane, including the blood brain barrier. See,for example, Hansch et al., J. Med. Chem. 11:1 (1968). Typical log Pvalues for the compounds described herein are generally greater thanabout −0.5, often are greater than about 0, and frequently are greaterthan about 0.5, and are typically less than about 3, often are less thanabout 2, and frequently are less than about 1.

In one embodiment, the compounds have the structure represented byFormula 1 below:

In the formula, Q^(I) is (CZ₂)_(u), Q^(II) is (CZ₂)_(v), Q^(III) is(CZ₂)_(w), and Q^(IV) is (CZ₂)_(x) where u, v, w and x are individually0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3. R is hydrogen, lower alkyl,acyl, alkoxycarbonyl or aryloxycarbonyl, preferably hydrogen or loweralkyl. When the value of u is 0, the value of v must be greater than 0,and, in the case of Formula 1, when the value of w is 0, the value of xmust be greater than 0. In addition, the values of u, v, w and x areselected such that the diazaspirocyclic ring contains 7, 8, 9, 10 or 11members, preferably 8, 9 or 10 members.

In another embodiment, the compounds are represented by Formula 2,above. In Formula 2 Q^(I) is (CZ₂)_(u), Q^(II) is (CZ₂)_(v), Q^(III) is(CZ₂)_(w), Q^(IV) is (CZ₂)_(x), Q^(V) is (CZ₂)_(y) and Q^(VI) is(CZ₂)_(z) where u, v, w, x, y and z are individually 0, 1, 2, 3 or 4,preferably 0, 1 or 2. The values of u, v, w, x, y and z are selectedsuch that the bridged diazaspirocyclic ring contains 8, 9, 10, 11, 12 or13 members, preferably 9, 10, 11 or 12 members. In the case of Formula2, the values w and x can be simultaneously 0. In addition, R ishydrogen, lower alkyl, acyl, alkoxycarbonyl or aryloxycarbonyl,preferably hydrogen or lower alkyl.

Each individual Z represents either hydrogen or a suitable non-hydrogensubstituent species (e.g., alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl orsubstituted arylalkyl; but preferably lower alkyl or aryl).

In both Formula 1 and Formula 2, Cy represents a suitable five- orsix-membered heteroaromatic ring. In one embodiment, Cy is a sixmembered ring of the formula:

Each of X, X′, X″, X′″ and X″″ is individually nitrogen, nitrogen bondedto oxygen (e.g., an N-oxide or N—O functionality) or carbon bonded to asubstituent species. No more than three of X, X′, X″, X′″ and X″″ arenitrogen or nitrogen bonded to oxygen, and it is preferred that only oneor two of X, X′, X″, X′″ and X″″ be nitrogen or nitrogen bonded tooxygen. In addition, it is highly preferred that not more than one of X,X′, X″, X′″ and X″″ be nitrogen bonded to oxygen; and it is preferredthat if one of those species is nitrogen bonded to oxygen, that speciesis X′″. Most preferably, X′″ is nitrogen. In certain preferredcircumstances, both X′ and X′″ are nitrogen. Typically, X, X″ and X″″are carbon bonded to a substituent species, and it is typical that thesubstituent species at X, X″ and X″″ are hydrogen. For certain otherpreferred compounds where X′″ is carbon bonded to a substituent speciessuch as hydrogen, X and X″ are both nitrogen. In certain other preferredcompounds where X′ is carbon bonded to a substituent species such ashydrogen, X and X′″ are both nitrogen.

In another embodiment, Cy is a five 5-membered heteroaromatic ring, suchas pyrrole, furan, thiophene, isoxazole, isothiazole, oxazole, thiazole,pyrazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and 1,2,4-triazole. Otherexamples of such rings are described in U.S. Pat. No. 6,022,868 toOlesen et al., the contents of which are incorporated herein byreference in their entirety. One way of depicting Cy is as follows:

where Y and Y″ are individually nitrogen, nitrogen bonded to asubstituent species, oxygen, sulfur or carbon bonded to a substituentspecies, and Y′ and Y′″ are nitrogen or carbon bonded to a substituentspecies. The dashed lines indicate that the bonds (between Y and Y′ andbetween Y′ and Y″) can be either single or double bonds. However, whenthe bond between Y and Y′ is a single bond, the bond between Y′ and Y″must be a double bond and vice versa. In cases in which Y or Y″ isoxygen or sulfur, only one of Y and Y″ is either oxygen or sulfur. Atleast one of Y, Y′, Y″ and Y′″ must be oxygen, sulfur, nitrogen ornitrogen bonded to a substituent species. It is preferred that no morethan three of Y, Y′, Y″ and Y′″ be oxygen, sulfur, nitrogen or nitrogenbonded to a substituent species. It is further preferred that at leastone, but no more than three, of Y, Y′, Y″ and Y′″ be nitrogen.

Substituent species associated with any of X, X′, X″, X′″, X″″, Y, Y′,Y″ and Y′″ (when any is carbon bonded to a substituent species ornitrogen bonded to a substituent species), typically have a sigma mvalue between about −0.3 and about 0.75, frequently between about −0.25and about 0.6; and each sigma m value individually can be 0 or not equalto zero; as determined in accordance with Hansch et al., Chem. Rev.91:165 (1991).

Examples of suitable substituent species associated with any of X, X′,X″, X′″, X″″, Y, Y′, Y″ and Y′″ (when any is carbon bonded to asubstituent species or nitrogen bonded to a substituent species),include hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl,arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br, or I), —OR′,—NR′R″, —CF₃, —CN, —NO₂, —C₂R′, —SR′, —N₃, —C(═O)NR′R″, —NR′C(═O)R″,—C(═O)R′, —C(═O)OR′, —OC(═O)R′, —O(CR′R″)_(r)C(═O)R′,O(CR′R″)_(r)NR″C(═O)R′, —O(CR′R″)_(r)NR″SO₂R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO₂R′, —SO₂NR′R″, and —NR′SO₂R″, where R′ and R″ are individuallyhydrogen, lower alkyl (e.g., straight chain or branched alkyl includingC₁-C₈, preferably C₁-C₅, such as methyl, ethyl, or isopropyl),cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl), and r isan integer from 1 to 6. R′ and R″ can combine to form a cyclicfunctionality. The term “substituted” as applied to alkyl, aryl,cycloalkyl and the like refers to the substituents described above,starting with halo and ending with —NR′SO₂R″.

Examples of suitable Cy groups include 3-pyridyl (unsubstituted orsubstituted in the 5 and/or 6 position(s) with any of the aforementionedsubstituents), 5-pyrimidinyl (unsubstituted or substituted in the 2position with any of the aforementioned substituents), 4 and5-isoxazolyl, 4 and 5-isothiazolyl, 5-oxazolyl, 5-thiazolyl,5-(1,2,4-oxadiazolyl), 2-(1,3,4-oxadiazolyl) or 3-(1,2,4-triazolyl).

Representative aryl groups include phenyl, naphthyl, furanyl, thienyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, and indolyl.Other representative aromatic ring systems are set forth in Gibson etal., J. Med. Chem. 39:4065 (1996). Any of these aromatic groupcontaining species can be substituted with at least one substituentgroup, such as those described above that are associated with x′ and thelike. Representative substituents include alkyl, aryl, halo, hydroxy,alkoxy, aryloxy or amino substituents.

Adjacent substituents of X, X′, X″, X′″, X″″, Y, Y′, Y″ and Y′″ (whensubstituents are present) can combine to form one or more saturated orunsaturated, substituted or unsubstituted carbocyclic or heterocyclicrings containing, but not limited to, ether, acetal, ketal, amine,ketone, lactone, lactam, carbamate, or urea functionalities.

The compounds can occur in stereoisomeric forms, including both singleenantiomers and racemic mixtures of such compounds, as well as mixturesof varying degrees of enantiomeric excess.

The compounds can be in a free base form or in a salt form (e.g., aspharmaceutically acceptable salts). Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as sulfate, phosphate, and nitrate; organic acid addition saltssuch as acetate, galactarate, propionate, succinate, lactate, glycolate,malate, tartrate, citrate, maleate, fumarate, methanesulfonate,p-toluenesulfonate, and ascorbate; salts with an acidic amino acid suchas aspartate and glutamate; alkali metal salts such as sodium andpotassium; alkaline earth metal salts such as magnesium and calcium;ammonium salt; organic basic salts such as trimethylamine,triethylamine, pyridine, picoline, dicyclohexylamine, andN,N′-dibenzylethylenediamine; and salts with a basic amino acid such aslysine and arginine. The salts can be in some cases hydrates or ethanolsolvates. The stoichiometry of the salt will vary with the nature of thecomponents. Representative salts are provided as described in U.S. Pat.Nos. 5,597,919 to Dull et al., 5,616,716 to Dull et al. and 5,663,356 toRuecroft et al., the disclosures of which are incorporated herein byreference in their entirety.

Representative compounds include the following:

-   7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane-   7-(5-pyrimidinyl)-1,7-diazaspiro[4.4]nonane-   7-(5-isoxazolyl)-1,7-diazaspiro[4.4]nonane-   7-(5-isothiazolyl)-1,7-diazaspiro[4.4]nonane-   7-(5-(1,2,4-oxadiazol)yl)-1,7-diazaspiro[4.4]nonane-   7-(2-(1,3,4-oxadiazol)yl)-1,7-diazaspiro[4.4]nonane-   7-(2-pyrazinyl)-1,7-diazaspiro[4.4]nonane-   7-(3-pyridazinyl)-1,7-diazaspiro[4.4]nonane-   7-(5-methoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   7-(5-cyclopentyloxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   7-(5-(4-hydroxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   7-(5-ethynyl-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   7-(6-chloro-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   7-(6-methoxy-3-pyridazinyl)-1,7-diazaspiro[4.4]nonane-   1-(3-pyridyl)-1,7-diazaspiro[4.4]nonane-   1-(5-pyrimidinyl)-1,7-diazaspiro[4.4]nonane-   1-(5-isoxazolyl)-1,7-diazaspiro[4.4]nonane-   1-(5-isothiazolyl)-1,7-diazaspiro[4.4]nonane-   1-(5-(1,2,4-oxadiazol)yl)-1,7-diazaspiro[4.4]nonane-   1-(2-(1,3,4-oxadiazol)yl)-1,7-diazaspiro[4.4]nonane-   1-(2-pyrazinyl)-1,7-diazaspiro[4.4]nonane-   1-(3-pyridazinyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-pyrimidinyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-isoxazolyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-isothiazolyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-(1,2,4-oxadiazol)yl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(2-(1,3,4-oxadiazol)yl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(2-pyrazinyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(3-pyridazinyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-methoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-cyclopentyloxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-(4-hydroxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(5-ethynyl-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(6-chloro-3-pyridyl)-1,7-diazaspiro[4.4]nonane-   1-methyl-7-(6-methoxy-3-pyridazinyl)-1,7-diazaspiro[4.4]nonane-   7-methyl-1-(3-pyridyl)-1,7-diazaspiro[4.4]nonane-   7-methyl-1-(5-pyrimidinyl)-1,7-diazaspiro[4.4]nonane-   7-methyl-1-(5-isoxazolyl)-1,7-diazaspiro[4.4]nonane-   7-methyl-1-(5-isothiazolyl)-1,7-diazaspiro[4.4]nonane-   7-methyl-1-(5-(1,2,4-oxadiazol)yl)-1,7-diazaspiro[4.4]nonane-   7-methyl-1-(2-(1,3,4-oxadiazol)yl)-1,7-diazaspiro[4.4]nonane-   7-methyl-1-(2-pyrazinyl)-1,7-diazaspiro[4.4]nonane-   7-methyl-1-(3-pyridazinyl)-1,7-diazaspiro[4.4]nonane-   2-(3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-(5-pyrimidinyl)-2,7-diazaspiro[4.4]nonane-   2-(5-isoxazolyl)-2,7-diazaspiro[4.4]nonane-   2-(5-isothiazolyl)-2,7-diazaspiro[4.4]nonane-   2-(5-(1,2,4-oxadiazol)yl)-2,7-diazaspiro[4.4]nonane-   2-(2-(1,3,4-oxadiazol)yl)-2,7-diazaspiro[4.4]nonane-   2-(2-pyrazinyl)-2,7-diazaspiro[4.4]nonane-   2-(3-pyridazinyl)-2,7-diazaspiro[4.4]nonane-   2-(5-methoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-(5-cyclopentyloxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-(5-phenoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-(5-(4-hydroxyphenoxy)-3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-(5-ethynyl-3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-(6-chloro-3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-(6-methoxy-3-pyridazinyl)-2,7-diazaspiro[4.4]nonane-   2-methyl-7-(3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-methyl-7-(5-methoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane-   2-methyl-7-(5-phenoxy-3-pyridyl)-2,7-diazaspiro[4.4]nonane-   6-(3-pyridyl)-1,6-diazaspiro[3.4]octane-   1-methyl-6-(3-pyridyl)-1,6-diazaspiro[3.4]octane-   2-(3-pyridyl)-2,5-diazaspiro[3.4]octane-   5-methyl-2-(3-pyridyl)-2,5-diazaspiro[3.4]octane-   6-(3-pyridyl)-1,6-diazaspiro[3.5]nonane-   1-methyl-6-(3-pyridyl)-1,6-diazaspiro[3.5]nonane-   2-(3-pyridyl)-2,5-diazaspiro[3.5]nonane-   5-methyl-2-(3-pyridyl)-2,5-diazaspiro[3.5]nonane-   2-(3-pyridyl)-2,6-diazaspiro[4.5]decane-   6-methyl-2-(3-pyridyl)-2,6-diazaspiro[4.5]decane-   7-(3-pyridyl)-1,7-diazaspiro[4.5]decane-   1-methyl-7-(3-pyridyl)-1,7-diazaspiro[4.5]decane-   8-(3-pyridyl)-1,8-diazaspiro[5.5]undecane-   1-methyl-8-(3-pyridyl)-1,8-diazaspiro[5.5]undecane

Other representative compounds of the present invention include thefollowing:

-   1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-ethoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-cyclopentyloxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-phenoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-isoxazolyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-isothiazolyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-(1,2,4-oxadiazol)yl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(2-(1,3,4-oxadiazol)yl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(2-pyrazinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(3-pyridazinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(5-ethynyl-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(6-chloro-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(6-methoxy-3-pyridazinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-   1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-methoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-cyclopentyloxy-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-phenoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-ethynyl-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(6-chloro-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(2-pyrazinyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(3-pyridazinyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(6-methoxy-3-pyridazinyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-isoxazolyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-isothiazolyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(5-(1,2,4-oxadiazol)yl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(2-(1,3,4-oxadiazol)yl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-   1′-(3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(5-methoxy-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(5-cyclopentyloxy-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(5-phenoxy-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(5-(4-hydroxyphenoxy)-3-pyridyl)-2H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(6-chloro-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(5-pyrimidinyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(2-pyrazinyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(3-pyridazinyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(6-methoxy-3-pyridazinyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(5-isoxazolyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(5-isothiazolyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(5-(1,2,4-oxadiazol)yl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]-   1′-(2-(1,3,4-oxadiazol)yl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]    II. Mehtods of preparing the Compounds

The compounds of Formulas 1 and 2 can be prepared using a general methodinvolving arylation of one amino group of an optionally protecteddiazaspiroalkane (Scheme 1). Arylation at N with an appropriate aryl, orpreferably heteroaryl, halide or triflate can be performed according tomethods known to those skilled in the art, for example, employing metal(e.g., copper or palladium compounds) catalysis. The preferred generalmethod in the present invention utilizes the teachings of Buchwald orHartwig (Buchwald et al, J. Org. Chem., 61: 7240 (1996); Hartwig et al.,J. Org. Chem., 64: 5575 (1999); see also Old et al., J. Am. Chem. Soc.120: 9722 (1998)), wherein an amine is treated with a palladium(0)catalyst, a phosphine ligand and base. Thus,1-benzyl-1,7-diazaspiro[4.4]nonane is reacted with 3-bromopyridine inthe presence of tris(dibenzylideneacetone)dipalladium(0),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and sodium tert-butoxide intoluene, to give 1-benzyl-7-(3-pyridyl)diazaspiro[4.4]nonane. Removal ofthe benzyl group by hydrogenation, over 10% palladium on carbon,provides 7-(3-pyridyl)-diazaspiro[4.4]nonane. Alternatively, one skilledin the art will recognize that various protecting group strategies canbe employed to provide products bearing an aryl group on nitrogen N′, asopposed to N (Reaction 1, Scheme 1). A particularly useful combinationof protecting groups in the present invention is benzyl and a carbamate,specifically, tert-butylcarbamate. Thus,1-benzyl-1,7-diazaspiro[4.4]nonane is converted into1-benzyl-7-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane by treatmentwith di-tert-butyl dicarbonate. Subsequent hydrogenation andpalladium-catalyzed arylation, with 3-bromopyridine, gives7-(tert-butoxycarbonyl)-1-(3-pyridyl)diazaspiro[4.4]nonane. Removal ofthe tert-butoxycarbonyl group, with hydrochloric acid, provides1-(3-pyridyl)-diazaspiro[4.4]nonane. Finally, in many cases where N andN′ are sterically dissimilar, and whenever N is tertiary (as in Reaction2, Scheme 1), selective arylation of N can be accomplished without firstprotecting N′. Thus, reaction of 1,7-diazaspiro[4.4]nonane with3-bromopyridine, under the palladium-catalyzed conditions reportedpreviously, gives almost exclusively7-(3-pyridyl)-diazaspiro[4.4]nonane.

It will be obvious to those skilled in the art that incorporation ofsubstituents on the heteroaryl ring introduced onto the diazaspiroalkanecan be readily realized. Such substituents can provide useful propertiesin and of themselves or serve as a handle for further syntheticelaboration. A suitably protected heteroaryl diazaspiroalkane can beelaborated to give a number of useful compounds possessing substituentson the heteroaryl ring. For example,1-benzyl-7-(5-bromo-3-pyridyl)-1,7-diazaspiro[4.4]nonane can be made byreacting 3,5-dibromopyridine with 1-benzyl-1,7-diazaspiro[4.4]nonaneaccording to procedures described previously. The conversion of1-benzyl-7-(5-bromo-3-pyridyl)diazaspiro[4.4]nonane into thecorresponding 5-amino-substituted compound can be accomplished by thegeneral method of Zwart et al., Recueil Trav. Chim. Pays-Bas 74: 1062(1955), in which the bromo compound was heated with aqueous ammonia inthe presence of a copper catalyst. 5-Alkylamino substituted compoundscan be prepared in a similar manner. 5-Ethynyl-substituted compounds canbe prepared from the 5-bromo compound by palladium catalyzed couplingusing 2-methyl-3-butyn-2-ol, followed by base-catalyzed (sodium hydride)removal of the acetone unit, according to the general techniquesdescribed in Cosford et al., J. Med. Chem. 39: 3235 (1996). The5-ethynyl analogs can be converted into the corresponding 5-ethenyl, andsubsequently to the corresponding 5-ethyl analogs by successivecatalytic hydrogenation reactions. The 5-azido-substituted analogs canbe prepared from the 5-bromo compound by reaction with lithium azide inN,N-dimethylformamide. 5-Alkylthio-substituted analogs can be preparedfrom the 5-bromo compound by reaction with an appropriate sodiumalkylmercaptide (sodium alkanethiolate), using techniques known to thoseskilled in the art of organic synthesis.

A number of other analogs, bearing substituents in the 5 position of thepyridine ring, can be synthesized from the corresponding aminocompounds, vide supra, via a 5-diazonium salt intermediate. Examples ofother 5-substituted analogs that can be produced from 5-diazonium saltintermediates include, but are not limited to: 5-hydroxy, 5-alkoxy,5-fluoro, 5-chloro, 5-iodo, 5-cyano, and 5-mercapto. These compounds canbe synthesized using the general techniques set forth in Zwart et al.,supra. For example,1-benzyl-7-(5-hydroxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane can beprepared from the reaction of the corresponding 5-diazonium saltintermediate with water. Likewise,1-benzyl-7-(5-alkoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonanes can be madefrom the reaction of the diazonium salt with alcohols. Appropriate5-diazonium salts can be used to synthesize cyano or halo compounds, aswill be known to those skilled in the art. 5-Mercapto substitutions canbe obtained using techniques described in Hoffman et al., J. Med. Chem.36: 953 (1993). The 5-mercaptan so generated can, in turn, be convertedto a 5-alkylthio substitutuent by reaction with sodium hydride and anappropriate alkyl bromide. Subsequent oxidation would then provide asulfone. 5-Acylamido analogs of the aforementioned compounds can beprepared by reaction of the corresponding 5-amino compounds with anappropriate acid anhydride or acid chloride using techniques known tothose skilled in the art of organic synthesis.

5-Hydroxy-substituted analogs of the aforementioned compounds can beused to prepare corresponding 5-alkanoyloxy-substituted compounds byreaction with the appropriate acid, acid chloride, or acid anhydride.Likewise, the 5-hydroxy compounds are precursors of both the 5-aryloxyand 5-heteroaryloxy via nucleophilic aromatic substitution at electrondeficient aromatic rings (e.g., 4-fluorobenzonitrile and2,4-dichloropyrimidine). Such chemistry is well known to those skilledin the art of organic synthesis. Ether derivatives can also be preparedfrom the 5-hydroxy compounds by alkylation with alkyl halides and asuitable base or via Mitsunobu chemistry, in which a trialkyl- ortriarylphosphine and diethyl azodicarboxylate are typically used. SeeHughes, Org. React. (N.Y.) 42: 335 (1992) and Hughes, Org. Prep. Proced.Int. 28: 127 (1996) for typical Mitsunobu conditions.

5-Cyano-substituted analogs of the aforementioned compounds can behydrolyzed to afford the corresponding 5-carboxamido-substitutedcompounds. Further hydrolysis results in formation of the corresponding5-carboxylic acid-substituted analogs. Reduction of the5-cyano-substituted analogs with lithium aluminum hydride yields thecorresponding 5-aminomethyl analogs. 5-Acyl-substituted analogs can beprepared from corresponding 5-carboxylic acid-substituted analogs byreaction with an appropriate alkyllithium using techniques known tothose skilled in the art of organic synthesis.

5-Carboxylic acid-substituted analogs of the aforementioned compoundscan be converted to the corresponding esters by reaction with anappropriate alcohol and acid catalyst. Compounds with an ester group atthe 5-pyridyl position can be reduced with sodium borohydride or lithiumaluminum hydride to produce the corresponding5-hydroxymethyl-substituted analogs. These analogs in turn can beconverted to compounds bearing an ether moiety at the 5-pyridyl positionby reaction with sodium hydride and an appropriate alkyl halide, usingconventional techniques. Alternatively, the 5-hydroxymethyl-substitutedanalogs can be reacted with tosyl chloride to provide the corresponding5-tosyloxymethyl analogs. The 5-carboxylic acid-substituted analogs canalso be converted to the corresponding 5-alkylaminoacyl analogs bysequential treatment with thionyl chloride and an appropriatealkylamine. Certain of these amides are known to readily undergonucleophilic acyl substitution to produce ketones. Thus, the so-calledWeinreb amides (N-methoxy-N-methylamides) react with aryllithiumreagents to produce the corresponding diaryl ketones. For example, seeSelnick et al., Tet. Lett. 34: 2043 (1993).

5-Tosyloxymethyl-substituted analogs of the aforementioned compounds canbe converted to the corresponding 5-methyl-substituted compounds byreduction with lithium aluminum hydride. 5-Tosyloxymethyl-substitutedanalogs of the aforementioned compounds can also be used to produce5-alkyl-substituted compounds via reaction with an alkyllithium reagent.5-Hydroxy-substituted analogs of the aforementioned compounds can beused to prepare 5-N-alkyl- or 5-N-arylcarbamoyloxy-substituted compoundsby reaction with N-alkyl- or N-arylisocyanates. 5-Amino-substitutedanalogs of the aforementioned compounds can be used to prepare5-alkoxycarboxamido-substituted compounds and 5-urea derivatives byreaction with alkyl chloroformate esters and N-alkyl- orN-arylisocyanates, respectively, using techniques known to those skilledin the art of organic synthesis.

Chemistries analogous to those described hereinbefore for thepreparation of 5-substituted pyridine analogs of diazaspiro compoundscan be devised for the synthesis of analogs bearing substituents in the2, 4, and 6 positions of the pyridine ring. For example, a number of 2-,4-, and 6-aminopyridyldiazaspiroalkanes can be converted to thecorresponding diazonium salt intermediates, which can be transformed toa variety of compounds with substituents at the 2, 4, and 6 positions ofthe pyridine ring as was described for the 5-substituted analogs above.The requisite 2-, 4-, and 6-aminopyridyl diazaspiroalkanes are availablevia the Chichibabin reaction of unsubstituted pyridyl diazaspiroalkanes(e.g., 1-benzyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane, describedpreviously) with sodium amide. Similar reactions are described inChemistry of Heterocyclic Compounds, Volume 14, part 3, pp. 3-5(Interscience Publishers, 1962) and by Lahti et al., J. Med. Chem. 42:2227 (1999).

After the desired heteroaryl ring functional group manipulation has beenaccomplished, the optional protecting group can be removed from thediazabicycle using appropriate conditions. Thus, for example,hydrogenolysis of1-benzyl-7-(5-alkoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane will generate7-(5-alkoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane. Those skilled in theart of organic chemistry will appreciate the necessity of pairingprotecting groups with the chemistries required to generate particularfunctionalities. In some cases it can be necessary, to retain aparticular functionality, to replace one protecting group with another.

In an alternative approach to the synthesis of pyridine-substitutedpyridyl diazaspiroalkanes, 3,5-dibromopyridine can be converted into thecorresponding 5-alkoxy-3-bromo- and 5-aryloxy-3-bromopyridines by theaction of sodium alkoxides or sodium aryloxides. Procedures such asthose described by Comins et al., J. Org. Chem. 55: 69 (1990) and Hertoget al., Recueil Trav. Chim. Pays-Bas 74: 1171 (1955) are used. This isexemplified by the preparation of7-(5-(4-methoxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane. Reactionof 3,5-dibromopyridine with sodium 4-methoxyphenoxide inN,N-dimethylformamide gives 3-bromo-5-(4-methoxyphenoxy)pyridine.Coupling of 3-bromo-5-(4-methoxyphenoxy)pyridine with1-benzyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane in the presence ofsodium tert-butoxide, and a catalytic amount oftris(dibenzylideneacetone)dipalladium(0) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, in toluene, followed byhydrogenolysis of the benzyl protecting group, will provide7-(5-(4-methoxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane.

Other aryl halides undergo the palladium-catalyzed coupling reactiondescribed previously. Thus 7-(5-pyrimidinyl)-1,7-diazaspiro[4.4]nonaneis prepared in a similar manner from 5-bromopyrimidine and optionally1-position protected 1,7-diazaspiro[4.4]nonane followed by deprotection,if necessary. This technology is especially applicable in cases, such as3-bromopyridine, 3,5-dibromopyridine, and 5-bromopyrimidine, where thearomatic ring is not activated toward nucleophilic aromaticsubstitution.

In some cases, coupling of the heteroaromatic ring to thediazaspirocycle can be accomplished without the use of palladiumcatalysis. Examples of both five- and six-membered heteroaromatic ringcompounds, which are activated toward nucleophilic aromaticsubstitution, are known by those skilled in the art of organicsynthesis. For example,7-(6-chloro-3-pyridazinyl)-1,7-diazaspiro[4.4]nonane can be synthesizedfrom 3,6-dichloropyridazine and 1,7-diazaspiro[4.4]nonane. Likewise,2,6-dicloropyrazine, and 2-bromothiazole will react with1,7-diazaspiro[4.4]nonane to give7-(6-chloro-2-pyrazinyl)-1,7-diazaspiro[4.4]nonane and7-(2-thiazoyl)-1,7-diazaspiro[4.4]nonane, respectively.

The coupling reactions described in this application, whether palladiumcatalyzed or not, are amenable to high through-put synthetic techniques.Thus a library of compounds of the present invention can be produced bycoupling, in a 96-well plate format, for instance, various haloareneswith various diazaspiro compounds.

Specific Diazaspiro Ring Systems

Optionally protected diazaspiroalkane intermediates used to prepare thecompounds of Formulas 1 and 2 can be prepared by numerous methods.Several of these diazaspiroalkane intermediates are known and can beprepared using prior art methods. However, the synthesis of theintermediates using palladium chemistry is new to the art, and thepharmaceutical activity of the intermediates was not appreciated in theprior art.

The compounds of Formula 1, where u=v=1, w=0 and x=3, possess a2,5-diazaspiro[3,4]octane core which can be prepared as depicted inScheme 2.

Alkylation of N-benzyl-L-proline ethyl ester (Aldrich Chemical), using astrong base such as lithium diisopropylamide (LDA) and the aminomethylequivalent cyanomethylbenzylamine, provides a beta-lactam, according tothe procedure reported by Overman, J. Am. Chem. Soc. 107:1698 (1985) andTet. Lett. 25: 1635 (1985). This can subsequently be reduced withlithium aluminum hydride to provide the 2,5-dibenzyl derivative of2,5-diazaspiro[3,4]octane. Removal of the benzyl protecting groups, byeither hydrogenation or oxidative cleavage with, for example, cericammonium nitrate, will produce 2,5-diazaspiro[3,4]octane. Alternatively,chemistry similar to that described in EP patent application 90117078.7(publication number EP 0 417 631) can be used to produce a geminalbis(hydroxymethyl) derivative and subsequently convert it to the desired2,5-diazaspiro[3,4]octane (Scheme 2). The subsequent palladium-catalyzedarylation, as described previously, would be expected to proceed withselectivity for the less sterically hindered azetidinyl nitrogen,producing 2-aryl-2,5-diazaspiro[3,4]octanes. The isomeric5-aryl-2,5-diazspiro[3,4]octanes can be made by first protecting theazetidinyl nitrogen (with, for instance, a carbamate) and thenperforming the arylation, followed by deprotection.

The compounds of Formula 1, wherein u=2, v=1, w=0 and x=3, possess the1,7-diazaspiro[4.4]nonane system which can be prepared according tonumerous methods, several of which are shown below in Scheme 3. In oneembodiment (Method A), a suitably protected proline ester, for exampleN-benzyl-L-proline ethyl ester, can be deprotonated with lithiumdiisopropylamide and allowed to react by Michael addition tonitroethylene. This provides methyl2-(2-nitroethyl)-1-benzylpyrrolidine-2-carboxylate. Subsequent reductionof the nitro group using Raney nickel, followed by lactamization bymethods known to those skilled in the art (for example, heating in asuitable solvent with or without an acidic or basic catalyst), provides1-benzyl-1,7-diazaspiro[4.4]nonan-6-one.

The 1,7-diazaspiro[4.4]nonane-6-one can alternatively be preparedaccording to one of several other methods reported in the literature.Such teachings indicate that a suitably protected proline ester can bedeprotonated with lithium diisopropylamide and allowed to react with analkylating agent such as chloroacetonitrile, then subjected to nitrilereduction and cyclization (Method B, Scheme 3) as reported by Culbertsonet al., J. Med. Chem. 33:2270 (1990).

Other teachings indicate that a suitably protected proline ester can bedeprotonated with lithium diisopropylamide and allowed to react with analkylating agent such as allyl bromide (Method C, Scheme 3). Theresulting olefin can then be oxidatively cleaved to an aldehyde, asreported by Genin et al., J. Org. Chem. 58:2334 (1993); Hinds et al., J.Med. Chem. 34:1777 (1991); Kim et al., J. Org. Chem. 61:3138(1996); EP0360390 and U.S. Pat. No. 5,733,912. The aldehyde can then be subjectedto reductive amination with an ammonium salt or primary aliphatic oraromatic amine, according to methods known to those skilled in the art.Alternatively, the aldehyde can be reduced to the corresponding alcoholand the alcohol then transformed to an amine by conversion to a leavinggroup, followed by displacement with the appropriate amine. This canalso be achieved by displacing the leaving group with an azide ion andsubsequently reduction to the primary amine using methods known to thoseskilled in the art. The alcohol can be converted to an amine usingMitsunobu conditions, as discussed previously. The alkyl 2-aminoethylpyrrolidine-2-carboxylate, obtained according to one of the methodsdescribed above, can be cyclized to a spirolactam by methods known tothose skilled in the art, such as heating in a suitable solvent with orwithout an acidic or basic catalyst.

The lactam obtained by any one of the above methods (Methods A, B or C)can be treated with a suitable reducing agent, such as lithium aluminumhydride, to provide the protected 1,7-diazaspiro[4.4]nonane, in thisexample, 1-benzyl-1,7-diazaspiro[4.4]nonane. The protecting group can beremoved using methods known those skilled in the art to provide thedesired 1,7-diazaspiro[4.4]nonane. Arylation at either nitrogen can beaccomplished using methods described herein.

Alternatively, the 1,7-diazaspiro[4.4]nonane core can also be preparedaccording to Scheme 4. The conversion of 1,4-dioxaspiro[4.5]decan-8-oneto 4-benzoyloxycyclohexanone can be readily achieved by those skilled inthe art. Subsequent transformation of 4-benzoyloxycyclohexanone to1,7-diazaspiro[4.4]nonane (through the intermediacy of 4-oxocaprolactam,as shown) can be performed according to the teachings of Majer et al.,Coll. Czech. Chem. Comm. 47:950 (1982).

The compounds of Formula 1, wherein u=2, v=1, w=1 and x=2, possess thesymmetrical 2,7-diazaspiro[4,4]nonane system which can be preparedaccording to Scheme 5. This method is reported by Overman et al., J.Org. Chem. 46: 2757 (1981) and Culbertson et al., J. Med. Chem. 33:2270(1990).

The compounds of Formula 1, wherein u=3, v=1, w=0 and x=3, possess the1,7-diazaspiro[4.5]decane system which can be prepared according toScheme 6. The teachings of Kim et al., J. Org. Chem. 61:3138 (1996),patent EP360390 and U.S. Pat. No. 5,733,912 indicate that a suitablyprotected proline ester (e.g., N-benzyl-L-proline ethyl ester) can bedeprotonated with lithium diisopropylamide and allowed to react with analkylating agent such as allyl bromide. U.S. Pat. No. 5,733,912 alsoteaches that hydroboration/oxidation of the allyl side chain can beperformed to provide the 2-(3-hydroxypropyl) group. Those skilled in theart will appreciate that the hydroxyl group can then be converted to anamino group by a number of methods, for example oxidation followed byreductive amination. Alternatively, a suitably protected proline estercan be deprotonated with lithium diisopropylamide and allowed to reactwith an alkylating agent such as diiodopropane. Conversion of theprimary iodide to an amine can then be performed according to knownmethods, for example treatment with ammonia in the presence of a coppercatalyst. The resulting amino ester can be cyclized to afford aprotected 1,7-diazaspiro[4.5]decan-6-one using any number of knownprocedures, for example heating in a suitable solvent in the presence orabsence of an acidic or basic catalyst, as discussed previously.Alternatively, the known 1,7-diaza-spiro[4.5]decan-6-one can be preparedaccording to the teachings of Loefas et al., J. Het. Chem. 21:583(1984), in which the ring contraction of2,10-diazabicyclo[4.4.0]dec-1-ene is used.

The 1,7-diazaspiro[4.5]decan-6-one, obtained by any of the abovemethods, can then be treated with a reducing agent, such as lithiumaluminum hydride, followed by removal of the protecting group, toprovide the desired 1,7-diazaspiro[4.5]decane. Arylation can then becarried out at either nitrogen using methods described herein.

The compounds of Formula 1, wherein u=2, v=1, w=0, and x=4, possess the2,6-diazaspiro[4.5]decane core which can be prepared according to themethod of Ciblat, et al., Tet. Lett. 42: 4815 (2001). Thus, commerciallyavailable 1-benzyl-3-pyrrolidinone can be reacted with2-methyl-2-(2-aminoethyl)-1,3-dioxolane (Islam and Raphael, J. Chem.Soc. 3151 (1955)) in an intramolecular Mannich reaction. The product,the ethylene ketal of 2-benzyl-2,10-diazaspiro[4,5]decan-7-one, can thenbe hydrolyzed to the ketone, using aqueous hydrochloric acid.Deoxygenation of the ketone can then be accomplished by standardmethods, such as conversion to the corresponding 1,3-dithiane, followedby treatment with Raney nickel. The 2-benzyl-2,6-diazaspiro[4,5]decanethus produced can be directly arylated on the 6-position nitrogen orconverted into 6-(tert-butoxycarbonyl)-2,6-diazaspiro[4,5]decane bytreatment with di-tert-butyl dicarbonate, followed by hydrogenation. Thelatter derivative can then be arylated at the 2-position nitrogen.Similar chemistry can be used to convert other azacyclic ketones intothe corresponding spirodiaza compounds. Thus, reaction of any of variousN-protected 3-azetidinones (the synthesis of which is described by Lall,et al., J. Org. Chem. 67: 1536 (2002) and Marchand, et al., Heterocycles49: 149 (1998)) with 2-methyl-2-(2-aminoethyl)-1,3-dioxolane, followedby deoxygenation (as described above), will produce the correspondingprotected 2,5-diazaspiro[3.5]nonane (Formula 1, wherein u=1, v=1, w=0,and x=4).

The compounds of Formula 1, wherein u=v=2, w=0, and x=3, possess the1,8-diazaspiro[4.5]decane core which can be prepared according to Scheme7. According to the teachings reported by Wittekind et al., J. Het.Chem. 9:11 (1972), a protected 4-piperidone can be converted to the4-nitropiperidine. Subsequent Michael addition with ethyl acrylate, forexample, followed by reduction of the nitro group with Raney nickel,provides the 1,8-diazaspiro[4.5]decan-2-one. This lactam can be reducedwith an appropriate reducing agent, such as lithium aluminum hydride,followed by removal of the protecting group, to provide the optionallysubstituted 1,8-diazaspiro[4.5]decane. Arylation on either nitrogen canbe accomplished using methods described herein.

The compounds of Formula 1, wherein u=2, v=1, and w=x=2, possess the2,8-diazaspiro[4.5]decane core which can be prepared according to Scheme8. According to various teachings (Helv. Chim. Acta 60: 1650 (1977);Smith et al., J. Med. Chem. 19:3772 (1995); Elliott et al., Biorg. Med.Chem. Lett. 8:1851 (1998)), a protected 4-piperidone can be converted tothe 4-piperidinylidene acetic acid ester via Wittig olefination.Subsequent Michael addition with the anion of nitromethane, followed byreduction of the nitro group and spontaneous cyclization with Raneynickel, provides the protected 2,8-diazaspiro[4.5]decan-3-one. Treatmentof the protected 2,8-diazaspiro[4.5]decan-3-one with a reducing agent,such as lithium aluminum hydride, followed by removal of the protectinggroup, provides the 2,8-diazaspiro[4.5]decane. Arylation can beaccomplished on either nitrogen using the methods described herein.

The compounds of Formula 1, wherein u=2, v=1, w=4 and x=0, possess the1,8-diazaspiro[5.5]decane core and can be prepared according to theprocedures utilized for the analogous 1,7-diazaspiro[4.4]nonanes bysubstituting pipecolinate ester for proline ester. Alternatively, theprocedure reported in Zhu et al., J. Org. Chem. 58:6451 (1993) can beemployed.

The compounds of Formula 1 wherein u=3, v=1, w=1 and x=3, possess thesymmetrical 2,8-diazaspiro[5.5]undecane core and can be preparedaccording to the procedures reported in Helv. Chim. Acta 36:1815 (1953),J. Org. Chem. 28:336 (1963) or, preferably, Culbertson et al., J. Med.Chem. 33:2270 (1990).

The compounds of Formula 1, wherein u=v=2 and w=x=2, possess thesymmetrical 3,9-diazaspiro[5.5]undecane core and can be preparedaccording to procedures reported in Rice et al., J. Het. Chem. 1:125(1964), U.S. Pat. No. 3,282,947, or J. Med. Chem. 8:62 (1965).

Single enantiomer compounds of the present invention can be made byvarious methods. One method, well known to those skilled in the art oforganic synthesis, involves resolution using diastereomeric salts.Compounds of the present invention contain basic nitrogen atoms and willreact with acids to form crystalline salts. Various acids, carboxylicand sulfonic, are commercially available in enantiomerically pure form.Examples include tartaric, dibenzoyl- and di-p-toluoyltartaric, andcamphorsulfonic acids. When any one of these or other single enantiomeracids is reacted with a racemic amine base, diastereomeric salts result.Fractional crystallization of the salts, and subsequent regeneration ofthe bases, results in enantiomeric resolution thereof.

Another means of separation involves conversion of the enantiomericmixture into diastereomeric amides or carbamates, using a chiral acid orchloroformate. Thus, when racemic7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane is coupled withN-(tert-butoxycarbonyl)-S-proline, using diphenyl chlorophosphate, andthe protecting group removed (with trifluoroacetic acid), the resultingdiastereomeric proline amides of 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonaneare separable by liquid chromatography. The separated amides are thentransformed into (+) and (−) 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane bythe Edman degradation.

Selective synthesis of single enantiomers can also be accomplished bymethods known to those skilled in the art. Such methods will vary as thechemistry used for construction of the diazaspiro rings varies. Forinstance, for the syntheses in which the alkylation of a prolinederivative is used to form the diazaspiro system (such as described forthe 1,7-diazaspiro[4.4]nonane system), the alkylation of proline can becarried out in a stereospecific manner. Thus, methods such as thosedescribed by Beck et al., Org. Synth. 72: 62 (1993) or Wang andGermanas, Synlett: 33 (1999) (and references therein) can be used tocontrol the stereochemistry of the alkylation step. Whenenantiomerically pure proline ester (commercially available fromAldrich) is used as the starting material for such a process, thealkylation product is also a single enantiomer. A variety ofelectrophiles can be used in such alkylations, including allyl halides,which have been useful in assembling spiro systems related to compoundsof the present invention Genin and Johnson, J. Amer. Chem. Soc. 114:8778 (1992).

Bridged Spiro Ring Systems

The compounds of Formula 2, wherein u=1, v=2, w=0, x=0, y=2 and z=2,possess the spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine] core andcan be prepared according to Scheme 9. The anion of ethyl nitroacetate,formed in the presence of an amine base, can be condensed withtetrahydropyran-4-one using the procedure reported in Formicola et al.,J. Org. Chem. 63:3528 (1998). Simultaneous reduction of the nitro groupand the olefin under catalytic hydrogenation conditions provides the2-(4-oxanyl)glycine ester. This compound can be treated with hydrobromicacid to afford a dibromide, which is cyclized under basic conditions tothe azabicyclo[2.2.1]heptane-7-carboxylic acid. Treatment of the acidwith ethanol and sulfuric acid provides the ethylazabicyclo[2.2.1]heptane-7-carboxylate. This compound is thendeprotonated with lithium diisopropylamide and reacted by Michaeladdition with nitroethylene to give the ethylaza-7-(2-nitroethyl)bicyclo[2.2.1]heptane-7-carboxylate. Reduction ofthe nitro group with Raney nickel, followed by spontaneous cyclization,affords the spirolactam. Treatment of the lactam with lithium aluminumhydride affords the spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine],which is subsequently arylated on the pyrrolidine nitrogen to producecompounds of the present invention.

The compounds of Formula 2, wherein u=1, v=2, w=1, x=0, y=1 and z=2,possess the spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] ringsystem and can be prepared according to Scheme 10. Conversion oftetrahydrofuran-3-ylmethanol (Aldrich) to 3-(bromomethyl)tetrahydrofurancan be achieved through mesylation and subsequent treatment with lithiumbromide. The reaction of ethyl glycinate with benzophenone imineprovides ethyl 3-aza-4,4-diphenyl-but-3-enoate which serves to bothprotect the amine and activate the methylene carbon toward alkylation.Alkylation of this imine can be performed, according to the method ofHansen, J. Org. Chem. 63:775 (1998), by deprotonating with potassiumtert-butoxide and reacting with the 3-(bromomethyl)tetrahydrofuran.Deprotection under acidic conditions gives the desired2-amino-3-(tetrahydrofuran-3-yl) propionic ester. Ring opening of thetetrahydrofuran can be achieved by treatment with hydrobromic acid toafford the dibromoamino acid intermediate, which, upon heating underbasic conditions, cyclizes to the1-azabicyclo[2.2.1]heptane-2-carboxylic acid. This acid is subsequentlyconverted to the ethyl ester, using ethanol and sulfuric acid.Alkylation is then performed by deprotonation with lithiumdiisopropylamide and reaction with nitroethylene. Subsequent reductionof the nitro group using Raney nickel, followed by lactamization bymethods known to those skilled in the art, gives thespiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]-2′-one. Treatment ofthe lactam with lithium aluminum hydride, gives the desiredspiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine], which issubsequently arylated on the pyrrolidine nitrogen to give compounds ofthe present invention.

The compounds of Formula 2, wherein u=1, v=2, w=1, x=0, y=2 and z=2,possess the spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine] core andcan be prepared in a manner similar to that for the correspondingspiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine], as seen in Scheme11. Ethyl quinuclidine-2-carboxylate can be generated from(4-bromomethyl)tetrahydropyran by the procedures discussed previouslyfor ethyl 1-azabicyclo[2.2.1]heptane-2-carboxylate. The requisite4-(bromomethyl)tetrahydropyran can be prepared according to proceduresfound in Burger, et al., J. Am. Chem. Soc. 72:5512 (1950), Thomas, etal., J. Pharm. Pharmacol. 15:167 (1963) and J. Am. Chem. Soc. 115:8401(1993). Ethyl quinuclidine-2-carboxylate is then deprotonated withlithium diisopropylamide and reacted with nitroethylene. Subsequenttreatment with Raney nickel gives directly the spirolactam,spiro[azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-2′-one, by reduction ofthe nitro group followed by spontaneous cyclization. This lactam is thenreduced with lithium aluminum hydride to provide the desiredspiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine], which is thenarylated on the pyrrolidine nitrogen.

Alternate Synthetic Methods

The compounds can be produced using varying methods. Alternatives to thepalladium catalyzed coupling protocol described above can be used. Forinstance, those skilled in the art of organic synthesis will recognizethat one or more of the nitrogen containing rings can be formed by anyone of many common amine syntheses. Thus, an arylamine can be reactedwith a protected cyclic amine derivative (see scheme 12), which containstwo reactive electrophiles, to generate an N-aryldiazaspiro compound. Avariety of electrophiles participate in such chemistry (e.g., halidesand sulfonates via nucleophilic displacement, aldehydes via reductiveamination, esters and other acid derivatives via acyl substitution,followed by reduction).

The requisite bis-electrophiles can be synthesized by many diversemethods. Schemes 2, 3 and 6 all incorporate such intermediates (inreaction with benzylamine or ammonia). Pedersen, et al., J. Org. Chem.58: 6966 (1993) and Berkowitz, et al., J. Org. Chem. 60: 1233 (1995)both report the alkylation of dianions of N-acyl α-aminoesters. Thesealkylations also can be used for synthesis of N-aryldiazaspirocompounds. Thus, dianion of commercially available (Acros) ethyl2-pyrrolidone-5-carboxylate can be alkylated with ethyl bromoacetate togenerate ethyl 5-(carboethoxymethyl)-2-pyrrolidone-5-carboxylate. Thesecond spiro ring can be formed by reacting ethyl5-(carboethoxymethyl)-2-pyrrolidone-5-carboxylate with an arylamine. Theresulting 2-aryl-2,6-diazspiro[4.4]nonane-1,3,7-trione can be reducedwith diborane to give 7-aryl-1,7-diazaspiro[4.4]nonane. Depending on thenature of the aryl group, the order of the synthetic steps can bechanged. Likewise, it can be necessary to incorporateprotection/deprotection steps into particular methods.

A wide variety of arylamines are available for use in the approachoutlined in Scheme 12. In addition to aminopyridines andaminopyrimidines, 3-aminoisoxazole is commercially available (Aldrich).This provides a means of synthesizing N-isoxazolyldiazaspiro compounds.The isomeric 4-aminoisoxazole can be made by reducing the correspondingnitro compound using the method described by Reiter, J. Org. Chem. 52:2714 (1987). Examples of other amino derivatives of 5-membered aromaticrings include 3-aminoisothiazole, made according to Holland, et al., J.Chem. Soc., 7277 (1965), and 4-aminoisothiazole, made according toAvalos, et al., An. Quim. 72: 922 (1976). Thus, a variety ofN-aryldiazaspiro compounds of the present invention, in which the arylgroup is a five-membered heterocycle, can be produced.

III. Pharmaceutical Compositions

The compounds described herein can be incorporated into pharmaceuticalcompositions and used to prevent a condition or disorder in a subjectsusceptible to such a condition or disorder, and/or to treat a subjectsuffering from the condition or disorder. The pharmaceuticalcompositions described herein include one or more compounds of Formulas1 or 2 and/or pharmaceutically acceptable salts thereof. Opticallyactive compounds can be employed as racemic mixtures or as pureenantiomers.

The manner in which the compounds are administered can vary. Thecompositions are preferably administered orally (e.g., in liquid formwithin a solvent such as an aqueous or non-aqueous liquid, or within asolid carrier). Preferred compositions for oral administration includepills, tablets, capsules, caplets, syrups, and solutions, including hardgelatin capsules and time-release capsules. Compositions may beformulated in unit dose form, or in multiple or subunit doses. Preferredcompositions are in liquid or semisolid form. Compositions including aliquid pharmaceutically inert carrier such as water or otherpharmaceutically compatible liquids or semisolids may be used. The useof such liquids and semisolids is well known to those of skill in theart.

The compositions can also be administered via injection, i.e.,intraveneously, intramuscularly, subcutaneously, intraperitoneally,intraarterially, intrathecally; and intracerebroventricularly.Intravenous administration is a preferred method of injection. Suitablecarriers for injection are well known to those of skill in the art, andinclude 5% dextrose solutions, saline, and phosphate buffered saline.The compounds can also be administered as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids).

The formulations may also be administered using other means, forexample, rectal administration. Formulations useful for rectaladministration, such as suppositories, are well known to those of skillin the art. The compounds can also be administered by inhalation (e.g.,in the form of an aerosol either nasally or using delivery articles ofthe type set forth in U.S. Pat. No. 4,922,901 to Brooks et al., thedisclosure of which is incorporated herein in its entirety); topically(e.g., in lotion form); or transdermally (e.g., using a transdermalpatch, using technology that is commercially available from Novartis andAlza Corporation). Although it is possible to administer the compoundsin the form of a bulk active chemical, it is preferred to present eachcompound in the form of a pharmaceutical composition or formulation forefficient and effective administration.

Exemplary methods for administering such compounds will be apparent tothe skilled artisan. The usefulness of these formulations may depend onthe particular composition used and the particular subject receiving thetreatment. These formulations may contain a liquid carrier that may beoily, aqueous, emulsified or contain certain solvents suitable to themode of administration.

The compositions can be administered intermittently or at a gradual,continuous, constant or controlled rate to a warm-blooded animal (e.g.,a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey),but advantageously are administered to a human being. In addition, thetime of day and the number of times per day that the pharmaceuticalformulation is administered can vary.

Preferably, upon administration, the active ingredients interact withreceptor sites within the body of the subject that affect thefunctioning of the CNS. More specifically, in treating a CNS disorder,preferable administration is designed to optimize the effect upon thoserelevant receptor subtypes that have an effect upon the functioning ofthe CNS, while minimizing the effects upon muscle-type receptorsubtypes. Other suitable methods for administering the compounds of thepresent invention are described in U.S. Pat. No. 5,604,231 to Smith etal. Preferably, the compositions are administered such that activeingredients interact with regions where cytokine production is affectedor occurs. The compounds described herein are very potent at treatingthese conditions or disorders (i.e., they affect cytokine productionand/or secretion at very low concentrations) and are very efficacious(i.e., they inhibit cytokine production and/or secretion to a relativelyhigh degree).

In certain circumstances, the compounds described herein can be employedas part of a pharmaceutical composition with other compounds intended toprevent or treat a particular disorder. In addition to effective amountsof the compounds described herein, the pharmaceutical compositions canalso include various other components as additives or adjuncts.Exemplary pharmaceutically acceptable components or adjuncts which areemployed in relevant circumstances include antioxidants, free-radicalscavenging agents, peptides, growth factors, antibiotics, bacteriostaticagents, immunosuppressives, anticoagulants, buffering agents,anti-inflammatory agents, anti-pyretics, time-release binders,anaesthetics, steroids, vitamins, minerals and corticosteroids. Suchcomponents can provide additional therapeutic benefit, act to affect thetherapeutic action of the pharmaceutical composition, or act towardspreventing any potential side effects which can be imposed as a resultof administration of the pharmaceutical composition.

The appropriate dose of the compound is that amount effective to preventoccurrence of the symptoms of the disorder or to treat some symptoms ofthe disorder from which the patient suffers. By “effective amount”,“therapeutic amount” or “effective dose” is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disorder.

When treating a CNS disorder, an effective amount of compound is anamount sufficient to pass across the blood-brain barrier of the subject,to bind to relevant receptor sites in the brain of the subject and toactivate relevant nicotinic receptor subtypes (e.g., provideneurotransmitter secretion, thus resulting in effective prevention ortreatment of the disorder). Prevention of the disorder is manifested bydelaying the onset of the symptoms of the disorder. Treatment of thedisorder is manifested by a decrease in the symptoms associated with thedisorder or an amelioration of the recurrence of the symptoms of thedisorder. Preferably, the effective amount is sufficient to obtain thedesired result, but insufficient to cause appreciable side effects.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount sufficient to activaterelevant receptors to effect neurotransmitter (e.g., dopamine) release,but the amount should be insufficient to induce effects on skeletalmuscles and ganglia to any significant degree. The effective dose ofcompounds will of course differ from patient to patient, but in generalincludes amounts starting where CNS effects or other desired therapeuticeffects occur but below the amount where muscular effects are observed.

The compounds, when employed in effective amounts in accordance with themethod described herein, are selective to certain relevant nicotinicreceptors, but do not significantly activate receptors associated withundesirable side effects at concentrations at least greater than thoserequired for eliciting the release of dopamine or otherneurotransmitters. By this is meant that a particular dose of compoundeffective in preventing and/or treating a CNS disorder is essentiallyineffective in eliciting activation of certain ganglionic-type nicotinicreceptors at concentration higher than 5 times, preferably higher than100 times, and more preferably higher than 1,000 times than thoserequired for activation of dopamine release. This selectivity of certaincompounds described herein against those ganglionic-type receptorsresponsible for cardiovascular side effects is demonstrated by a lack ofthe ability of those compounds to activate nicotinic function of adrenalchromaffin tissue at concentrations greater than those required foractivation of dopamine release.

For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount of at least about 1,often at least about 10, and frequently at least about 25 fig/24hr/patient. The effective dose generally does not exceed about 500,often does not exceed about 400, and frequently does not exceed about300 μg/24 hr/patient. In addition, administration of the effective doseis such that the concentration of the compound within the plasma of thepatient normally does not exceed 500 ng/mL and frequently does notexceed 100 ng/mL.

The compounds described herein, when employed in effective amounts inaccordance with the methods described herein, can provide some degree ofprevention of the progression of CNS disorders, ameliorate symptoms ofCNS disorders, and ameliorate to some degree the recurrence of CNSdisorders. The effective amounts of those compounds are typically belowthe threshold concentration required to elicit any appreciable sideeffects, for example those effects relating to skeletal muscle. Thecompounds can be administered in a therapeutic window in which certainCNS disorders are treated and certain side effects are avoided. Ideally,the effective dose of the compounds described herein is sufficient toprovide the desired effects upon the CNS but is insufficient (i.e., isnot at a high enough level) to provide undesirable side effects.Preferably, the compounds are administered at a dosage effective fortreating the CNS disorders but less than ⅕, and often less than 1/10,the amount required to elicit certain side effects to any significantdegree.

Most preferably, effective doses are at very low concentrations, wheremaximal effects are observed to occur, with a minimum of side effects.Concentrations, determined as the amount of compound per volume ofrelevant tissue, typically provide a measure of the degree to which thatcompound affects cytokine production. Typically, the effective dose ofsuch compounds generally requires administering the compound in anamount of less than 5 mg/kg of patient weight. Often, the compounds ofthe present invention are administered in an amount from less than about1 mg/kg patent weight and usually less than about 100 μg/kg of patientweight, but frequently between about 10 μg to less than 100 μg/kg ofpatient weight. For compounds that do not induce effects on muscle-typenicotinic receptors at low concentrations, the effective dose is lessthan 5 mg/kg of patient weight; and often such compounds areadministered in an amount from 50 μg to less than 5 mg/kg of patientweight. The foregoing effective doses typically represent that amountadministered as a single dose, or as one or more doses administered overa 24-hour period.

For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount of at least about 1,often at least about 10, and frequently at least about 25 μg/24hr/patient. For human patients, the effective dose of typical compoundsrequires administering the compound which generally does not exceedabout 500, often does not exceed about 400, and frequently does notexceed about 300 μg/24 hr/patient. In addition, the compositions areadvantageously administered at an effective dose such that theconcentration of the compound within the plasma of the patient normallydoes not exceed 500 pg/mL, often does not exceed 300 pg/mL, andfrequently does not exceed 100 pg/mL. When employed in such a manner,the compounds are dose dependent, and, as such, inhibit cytokineproduction and/or secretion when employed at low concentrations but donot exhibit those inhibiting effects at higher concentrations. Thecompounds exhibit inhibitory effects on cytokine production and/orsecretion when employed in amounts less than those amounts necessary toelicit activation of relevant nicotinic receptor subtypes to anysignificant degree.

IV. Methods of using the Compounds and/or Pharmaceutical Compositions

The compounds can be used to treat those types of conditions anddisorders for which other types of nicotinic compounds have beenproposed as therapeutics. See, for example, Williams et al., Drug NewsPerspec. 7(4):205 (1994), Arneric et al., CNS Drug Rev. 1(1):1 (1995),Arneric et al., Exp. Opin. Invest. Drugs 5(1):79 (1996), Bencherif etal., J. Pharmacol. Exp. Ther. 279:1413 (1996), Lippiello et al., J.Pharmacol. Exp. Ther. 279:1422 (1996), Damaj et al., J. Pharmacol. Exp.Ther. 291:390 (1999); Chiari et al., Anesthesiology 91:1447 (1999);Lavand'homme and Eisenbach, Anesthesiology 91:1455 (1999); Holladay etal., J. Med. Chem. 40(28):4169 (1997), Bannon et al., Science 279:77(1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat. Nos. 5,583,140to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al., and U.S.Pat. No. 5,604,231 to Smith et al., the disclosures of which areincorporated herein by reference in their entirety.

The compounds can also be used as adjunct therapy in combination withexisting therapies in the management of the aforementioned types ofdiseases and disorders. In such situations, it is preferable toadminister the active ingredients to in a manner that optimizes effectsupon abnormal cytokine production, while minimizing effects uponreceptor subtypes such as those that are associated with muscle andganglia. This can be accomplished by targeted drug delivery and/or byadjusting the dosage such that a desired effect is obtained withoutmeeting the threshold dosage required to achieve significant sideeffects.

Treatment of CNS Disorders

The compounds described herein are effective at treating a wide varietyof CNS disorders. Examples of CNS disorders that can be treated inaccordance with the present invention include pre-senile dementia (earlyonset Alzheimer's disease), senile dementia (dementia of the Alzheimer'stype), Lewy Body dementia, HIV-dementia, multiple cerebral infarcts,Parkinsonism including Parkinson's disease, Pick's disease, Huntington'schorea, tardive dyskinesia, hyperkinesia, mania, attention deficitdisorder, anxiety, depression, mild cognitive impairment, dyslexia,schizophrenia and Tourette's syndrome.

CNS disorders can be treated and/or prevented by administering to apatient an amount of a compound or pharmaceutical composition effectivefor providing some degree of prevention of the progression of a CNSdisorder (i.e., provide protective effects), amelioration of thesymptoms of a CNS disorder, and amelioration of the recurrence of a CNSdisorder. The method involves administering an effective amount of acompound selected from the general formulae, which are set forthhereinbefore.

Other Disorders

In addition to treating CNS disorders, the pharmaceutical compositionscan be used to prevent or treat certain other conditions, diseases anddisorders. Examples include neurodegenerative diseases, autoimmunedisorders such as Lupus, disorders associated with cytokine release,anti-inflammatory uses, as well as those indications set forth in PCT WO98/25619. The pharmaceutical compositions can ameliorate many of thesymptoms associated with those conditions, diseases and disorders.

Inhibition of cytokine release is desirable in the treatment ofcachexia, inflammation, neurodegenerative diseases, viral infection, andneoplasia. The cachexia is often secondary to infection (e.g., as occursin AIDS, AIDS-related complex and neoplasia) or to cancer therapy.Examples of inflammatory disorders that can be treated include acutecholangitis, aphthous stomatitis, asthma, ulcerative colitis,inflammatory bowel disease, pouchitis, viral pneumonitis and arthritis(e.g., rheumatoid arthritis and osteoarthritis).

The pharmaceutical compositions can also be used as anti-infectiousagents (e.g, for treating bacterial, fungal and viral infections, aswell as the effects, such as sepsis, of other types of toxins).

The compounds can be used as analgesics, to treat convulsions such asthose that are symptomatic of epilepsy, to treat conditions such assyphillis and Creutzfeld-Jakob disease.

The compounds can also be appropriately synthesized and used as orwithin pharmaceutical compositions that are used as diagnostic probes.

The compounds useful according to the method of the present inventionhave the ability to bind to, and in most circumstances, cause activationof, nicotinic cholinergic receptors of the brain of the patient (e.g.,such as those receptors that modulate dopamine release). As such, suchcompounds have the ability to express nicotinic pharmacology, and inparticular, to act as nicotinic agonists. The receptor binding constantsof typical compounds useful in carrying out the present inventiongenerally exceed about 0.1 nM, often exceed about 1 nM, and frequentlyexceed about 10 nM. The receptor binding constants of such typicalcompounds generally are less than about 1 μM often are less than about100 nM, and frequently are less than about 50 nM. Receptor bindingconstants provide a measure of the ability of the compound to bind tohalf of the relevant receptor sites of certain brain cells of thepatient. See, Cheng, et al., Biochem. Pharmacol. 22: 3099 (1973).

The compounds useful according to the method of the present inventionhave the ability to demonstrate a nicotinic function by effectivelyeliciting ion flux through, and/or neurotransmitter secretion from,nerve ending preparations (e.g., thalamic or striatal synaptosomes). Assuch, such compounds have the ability to cause relevant neurons tobecome activated, and to release or secrete acetylcholine, dopamine, orother neurotransmitters. Generally, typical compounds useful in carryingout the present invention effectively provide for relevant receptoractivation in amounts of at least about 30 percent, often at least about50 percent, and frequently at least about 75 percent, of that maximallyprovided by (S)-(−)-nicotine. Generally, typical compounds useful incarrying out the present invention are more potent than (S)-(−)-nicotinein eliciting relevant receptor activation. Generally, typical compoundsuseful in carrying out the present invention effectively provide for thesecretion of dopamine in amounts of at least about 50 percent, often atleast about 75 percent, and frequently at least about 100 percent, ofthat maximally provided by (S)-(−)-nicotine. Certain compounds of thepresent invention can provide secretion of dopamine in an amount whichcan exceed that maximally provided by (S)-(−)-nicotine. Generally,typical compounds useful in carrying out the present invention are lesspotent than (S)-(−)-nicotine in eliciting neurotransmitter secretion,such as dopamine secretion.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, lack theability to elicit activation of nicotinic receptors of human muscle toany significant degree. In that regard, the compounds of the presentinvention demonstrate poor ability to cause isotopic rubidium ion fluxthrough nicotinic receptors in cell preparations expressing muscle-typenicotinic acetylcholine receptors. Thus, such compounds exhibit receptoractivation constants or EC50 values (i.e., which provide a measure ofthe concentration of compound needed to activate half of the relevantreceptor sites of the skeletal muscle of a patient) which are extremelyhigh (i.e., greater than about 100 μM). Generally, typical preferredcompounds useful in carrying the present invention activate isotopicrubidium ion flux by less than 10 percent, often by less than 5 percent,of that maximally provided by S(−) nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, areselective to certain relevant nicotinic receptors, but do not causesignificant activation of receptors associated with undesirable sideeffects. By this is meant that a particular dose of compound resultingin prevention and/or treatment of a CNS disorder, is essentiallyineffective in eliciting activation of certain ganglionic-type nicotinicreceptors. This selectivity of the compounds of the present inventionagainst those receptors responsible for cardiovascular side effects isdemonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue. As such, such compoundshave poor ability to cause isotopic rubidium ion flux through nicotinicreceptors in cell preparations derived from the adrenal gland.Generally, typical preferred compounds useful in carrying out thepresent invention activate isotopic rubidium ion flux by less than 10percent, often by less than 5 percent, of that maximally provided byS(−) nicotine.

Compounds of the present invention, when employed in effective amountsin accordance with the method of the present invention, are effectivetowards providing some degree of prevention of the progression of CNSdisorders, amelioration of the symptoms of CNS disorders, andamelioration to some degree of the recurrence of CNS disorders. However,such effective amounts of those compounds are not sufficient to elicitany appreciable side effects, as is demonstrated by decreased effects onpreparations believed to reflect effects on the cardiovascular system,or effects to skeletal muscle. As such, administration of compounds ofthe present invention provides a therapeutic window in which treatmentof certain CNS disorders is provided, and side effects are avoided. Thatis, an effective dose of a compound of the present invention issufficient to provide the desired effects upon the CNS, but isinsufficient (i.e., is not at a high enough level) to provideundesirable side effects. Preferably, effective administration of acompound of the present invention resulting in treatment of CNSdisorders occurs upon administration of less than ⅓, frequently lessthan ⅕, and often less than 1/10, that amount sufficient to cause anyside effects to a significant degree.

The following examples are provided to illustrate the present invention,and should not be construed as limiting thereof. In these examples, allparts and percentages are by weight, unless otherwise noted. Reactionyields are reported in mole percentages. Several commercially availablestarting materials are used throughout the following examples.3-Bromopyridine, 3,5-dibromopyridine, 5-bromonicotinic acid,5-bromopyrimidine, and 4-penten-2-ol were obtained from Aldrich ChemicalCompany or Lancaster Synthesis Inc. 2-Amino-5-bromo-3-methylpyridine waspurchased from Maybridge Chemical Company Ltd. (R)-(+)-propylene oxidewas obtained from Fluka Chemical Company, and (S)-(−)-propylene oxidewas obtained from Aldrich Chemical Company. Column chromatography wasdone using either Merck silica gel 60 (70-230 mesh) or aluminum oxide(activated, neutral, Brockmann I, standard grade, about 150 mesh).Pressure reactions were done in a heavy wall glass pressure tube (185 mLcapacity), with Ace-Thread, and plunger valve available from Ace GlassInc. Reaction mixtures were typically heated using a high-temperaturesilicon oil bath, and temperatures refer to those of the oil bath. Thefollowing abbreviations are used in the following examples: CHCl₃ forchloroform, CH₂Cl₂ for dichloromethane, CH₃OH for methanol, DMF forN,N-dimethylformamide, and EtOAc for ethyl acetate, THF fortetrahydrofuran, and Et₃N for triethylamine.

V. Assays (Need New Descriptions Here)

Binding Assay

The ability of the compounds to bind to relevant receptor sites wasdetermined in accordance with the techniques described in U.S. Pat. No.5,597,919 to Dull et al. Inhibition constants (K_(i) values) werecalculated from the IC₅₀ values using the method of Cheng et al.,Biochem. Pharmacol. 22:3099 (1973). For the a4β2 subtype, the Ki valuefor each of the examples in this application was less than 1 μM,indicating that compounds of the present invention bind tightly to thereceptor.

Determination of Log P Value

Log P values, which have been used to assess the relative abilities ofcompounds to pass across the blood-brain barrier (Hansch, et al., J.Med. Chem. 11: 1 (1968)), were calculated using the Cerius² softwarepackage Version 3.5 by Molecular Simulations, Inc.

Determination of Dopamine Release

Dopamine release was measured using the techniques described in U.S.Pat. No. 5,597,919 to Dull et al. Release is expressed as a percentageof release obtained with a concentration of (S)-(−)-nicotine resultingin maximal effects. Reported EC₅₀ values are expressed in nM, andE_(max) values represent the amount released relative to(S)-(−)-nicotine on a percentage basis.

Determination of Rubidium Ion Release

Rubidium release was measured using the techniques described inBencherif et al., JPET 279: 1413-1421 (1996). Reported EC₅₀ values areexpressed in nM, and E_(max) values represent the amount of rubidium ionreleased relative to 300 μM tetramethylammonium ion, on a percentagebasis.

Determination of Interaction with Muscle Receptors

The determination of the interaction of the compounds with musclereceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis.

Determination of Interaction with Ganglion Receptors

The determination of the interaction of the compounds with ganglionicreceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis.

Selectivity

The selectivity of the compounds for a given receptor can be evaluatedby comparing the binding of the compounds to different receptors usingknown methodology.

VI. Synthetic Examples

The following synthetic examples are provided to illustrate the presentinvention and should not be construed as limiting the scope thereof. Inthese examples, all parts and percentages are by weight, unlessotherwise noted. Reaction yields are reported in mole percentage.

Example 1

Sample No. 1 is 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane dihydrochloride,which was prepared according to the following techniques:

Nitroethylene

Nitroethylene was prepared accordingly to the procedure reported byRanganathan, et al., J. Org. Chem. 45: 1185 (1980).

Ethyl 2-(2-nitroethyl)-1-benzylpyrrolidine-2-carboxylate

Under a nitrogen atmosphere, a solution of diisopropylamine (4.34 g,6.01 mL, 42.9 mmol) in dry THF (50 mL) was cooled in an ice bath asn-butyllithium (17.1 mL of 2.5 M in hexane, 42.8 mmol) was added bysyringe. The ice bath was removed and the solution of lithiumdiisopropylamide was first warmed to ambient temperature and thentransferred by cannula into a stirred solution of ethyl (S)-N-benzylpyrrolidine-2-carboxylate (10.0 g, 42.9 mmol) (Fluka) in dry THF (50mL), held at −78° C. under nitrogen. The addition took 10 min. Afterstirring an additional 30 min at −78° C., the enolate solution wastreated (via cannula) with a solution of nitroethylene (3.13 g, 42.9mmol) in dry THF (20 mL). The mixture was then stirred for 1 h at −78°C. Saturated aqueous ammonium chloride solution was then added (at −78°C.), and the mixture was warmed to ambient temperature and extracted theethyl acetate (4×30 mL). The extracts were dried (K₂CO₃) andconcentrated by rotary evaporation. The residue was purified bychromatography on a Merck silica gel 60 (70-230 mesh) column with 9:1(v/v) hexane/ethyl acetate. Concentration of selected fractions gave10.0 g (76.3%) of viscous, tan oil.

6-Benzyl-2,6-diazaspiro[4.4]nonan-1-one

Raney nickel (˜2 g) was added to a solution of ethyl2-(2-nitroethyl)-1-benzylpyrrolidine-2-carboxylate (6.00 g, 19.6 mmol)in absolute ethanol (200 mL) in a hydrogenation bottle. The mixture wasshaken for 12 h under a hydrogen atmosphere (50 psi) in a Parrhydrogenation apparatus, filtered through a Celite pad and concentratedby rotary evaporation. GCMS analysis indicated that the hydrogenationproduct was a mixture of the primary amine and the lactam resulting fromcyclization of the amine onto the ester. The mixture was dissolved intoluene (150 mL). A catalytic amount of p-toluenesulfonic acid (˜30 mg)was added and the mixture was heated at reflux under a nitrogenatmosphere for 24 h. Upon evaporation of the toluene, the residue (nowentirely lactam, by GCMS) crystallized to give 4.20 g (93.1%) of tansolid (mp 152-153° C.).

1-Benzyl-1,7-diazaspiro[4.4]nonane

Lithium aluminum hydride (1.98 g, 52.2 mmol) was added in portions,under argon, to a ice bath cooled solution of6-benzyl-2,6-diazaspiro[4.4]nonan-1-one (4.00 g, 17.4 mmol) in dry THF(100 mL). The addition funnel was replaced with a reflux condenser, andthe mixture was heated at reflux for 24 h. The mixture was cooled to 0°C. and treated drop-wise (caution: exothermic reaction) with 10 Maqueous sodium hydroxide until hydrogen evolution ceased and thealuminate salts were granular. The mixture was stirred 1 h at 0° C. andfiltered through Celite. The filtrate was dried (K₂CO₃) andconcentrated, leaving 3.60 g (95.7%) of viscous, colorless liquid.

1-Benzyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane

A mixture of 1-benzyl-1,7-diazaspiro[4.4]nonane (2.00 g, 9.26 mmol),3-bromopyridine (1.38 g, 8.73 mmol), potassium tert-butoxide (2.50 g,22.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.318 g, 0.347mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.324 g, 0.520 mmol)and dry toluene (50 mL) was placed in a pressure tube under argon. Themixture was stirred and heated at 90° C. (bath temperature) for 24 h andcooled. Water (20 mL) was added and the mixture was extracted with ethylacetate (6×25 mL). The extracts were dried (K₂CO₃) and concentrated.Column chromatography of the residue on Merck silica gel 60 (70-230mesh), with 6:4 (v/v) chloroform/acetone, gave 1.80 g (66.2%) of lightbrown oil, after concentration of selected fractions.

7-(3-Pyridyl)-1,7-diazaspiro[4.4]nonane dihydrochloride

Aqueous hydrochloric acid (0.5 mL of 12 M) and 10% palladium on carbon(0.100 g) were added to a solution of1-benzyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane (1.0 g, 3.41 mmol) inmethanol (30 mL). The mixture was shaken under a hydrogen atmosphere (50psi) in a Parr hydrogenation apparatus for 24 h and filtered throughCelite. The filtrate was concentrated by rotary evaporation and columnchromatographed on Merck silica gel 60 (70-230 mesh). Elution with0.01:1:9 (v/v) aqueous ammonia/methanol/chloroform, and concentration ofselected fractions, gave 0.650 g (93.8%) of viscous, brown oil. Aportion (300 mg, 1.48 mmol) of this material was treated with aqueoushydrochloric acid (2 mL). The water was azeotropically removed byrepeated treatment with small volumes of ethanol (˜5 mL) and rotaryevaporation. The resulting solid was recrystallized from hot isopropanolto give 360 mg (88.2%) of fine tan crystals.

Example 2

Sample 2 is 1-(3-pyridyl)-1,7-diaza-spiro[4.4]nonane dihydrochloride,which was prepared according to the following techniques:

tert-Butyl 6-benzyl-2,6-diazaspiro[4.4]nonane-2-carboxylate

Di-t-butyl dicarbonate (1.45 g, 6.64 mmol) was added to a solution of1-benzyl-1,7-diazaspiro[4.4]nonane (1.30 g, 6.01 mmol) and triethylamine(1 mL) in dichloromethane (25 mL), and the mixture was stirred atambient temperature overnight. The mixture was poured into saturatedaqueous sodium bicarbonate (10 mL) and extracted with chloroform (4×25mL). The extracts were dried (K₂CO₃) and concentrated by rotaryevaporation. The residue was column chromatographed on Merck silica gel60 (70-230 mesh), eluting with 95:5:1 chloroform/methanol/aqueousammonia, to give 1.85 g (97.4%) of viscous, colorless oil, afterconcentration of selected fractions.

tert-Butyl 2,6-diazaspiro[4.4]nonane-2-carboxylate

A solution of t-butyl 6-benzyl-2,6-diazaspiro[4.4]nonane-2-carboxylate(1.70 g, 5.37 mmol) in methanol (30 mL) was mixed with 10% palladium oncarbon (50 mg). The mixture was shaken under a hydrogen atmosphere (50psi) in a Parr hydrogenation apparatus for 8 h and filtered throughCelite. The filtrate was concentrated by rotary evaporation and highvacuum treatment, leaving 1.26 g of viscous, light brown oil (>100%),which was of sufficient purity to be used in the subsequent reaction.

tert-Butyl 6-(3-pyridyl)-2,6-diazaspiro[4.4]nonane-2-carboxylate

A mixture of tert-butyl 2,6-diazaspiro[4.4]nonane-2-carboxylate (1.00 g,˜4.4 mmol), 3-bromopyridine (0.736 g, 4.66 mmol), potassiumtert-butoxide (1.22 g, 10.9 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.155 g, 0.169 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.158 g, 0.254 mmol) anddry toluene (25 mL) was placed in a pressure tube under argon. Themixture was stirred and heated at 180° C. (bath temperature) for 8 h andcooled. Thin layer analysis indicated that very little conversion hadtaken place. A second charge, equal in quantity to the first, of allreagents except the tert-butyl 2,6-diazaspiro[4.4]nonane-2-carboxylatewas added to pressure tube and the tube was returned to the bath foranother 8 h. Again relatively little reaction seemed to have occurred,so a third charge of reagents was added and heating (at 180° C.) wascontinued for a third 8 h period. Water (20 mL) was added and themixture was extracted with ethyl acetate (6×25 mL). The extracts weredried (K₂CO₃) and concentrated. Column chromatography of the residue onMerck silica gel 60 (70-230 mesh), with 6:4 (v/v) chloroform/acetone,gave 150 mg (˜11%) of light brown oil, after concentration of selectedfractions.

1-(3-Pyridyl)-1,7-diazaspiro[4.4]nonane dihydrochloride

A solution of tert-butyl6-(3-pyridyl)-2,6-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 0.330mmol) in dichloromethane (5 mL) was rapidly stirred with 1 mL of 12 Mhydrochloric acid at ambient temperature for 1 h, during which time thebiphasic mixture became monophasic. The dichloromethane was evaporated,and the residue was dissolved in water (3 mL) and made strongly basic(pH 9) with potassium carbonate. The mixture was saturated with sodiumchloride and extracted with chloroform (4×10 mL). The extracts weredried (K₂CO₃) and concentrated, first by rotary evaporation and then byhigh vacuum treatment. The viscous brown oil which resulted was 98% pureby GCMS and weighed 50 mg (73%). A sample of this free base (40 mg, 020mmol) was dissolved in 10 drops of 12 M hydrochloric acid. The water wasazeotropically removed by repeated treatment with small volumes ofethanol (˜5 mL) and rotary evaporation. The resulting solid wasrecrystallized from hot isopropanol to give 40 mg (72%) of fine tancrystals (mp 170-175° C.).

Example 3

Sample 3 is 1-methyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane, which wasprepared according to the following techniques:

1-Methyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane

7-(3-Pyridyl)-1,7-diazaspiro[4.4]nonane (30 mg, 0.15 mmol) was dissolvedin 98% formic acid (0.5 mL) and formaldehyde (1 mL, 28% aqueoussolution). The reaction mixture was heated to reflux for 8 h. Thereaction mixture was cooled to room temperature, basified with saturatedaqueous sodium bicarbonate to pH 9-10 and extracted with chloroform (4×3mL). The combined chloroform extracts were dried (K₂CO₃), filtered andconcentrated on a rotary evaporator to afford 30 mg of the desiredcompound (93.6%) as a light brown liquid.

Example 4

Sample 4 is 1-methyl-7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane,which was prepared according to the following techniques:

5-bromo-3-ethoxypyridine

Under a nitrogen atmosphere, sodium (4.60 g, 200 mmol) was added toabsolute ethanol (100 mL) at 0-5° C., and the stirring mixture wasallowed to warm to ambient temperature over 18 h. To the resultingsolution was added 3,5-dibromopyridine (31.5 g, 133 mmol), followed byDMF (100 mL). The mixture was heated at 70° C. for 48 h. The brownmixture was cooled, poured into water (600 mL), and extracted with ether(3×500 mL). The combined ether extracts were dried (Na₂SO₄), filtered,and concentrated by rotary evaporation. Purification by vacuumdistillation afforded 22.85 g (85.0%) of an oil, bp 89-90° C. at 2.8 mmHg (lit. bp 111° C. at 5 mm Hg, see K. Clarke, et al., J. Chem. Soc.1885 (1960)).

1-Benzyl-7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane

1-Benzyl-1,7-diazaspiro[4.4]nonane (500.0 mg, 2.4 mmol) was dissolved indry toluene (15 mL) in a 50 mL round bottom flask equipped with amagnetic stirring bar. Nitrogen was bubbled through the solution in aslow stream. To the stirring solution was added 3-bromo-5-ethoxypyridine(513.8 mg, 2.55 mmol), potassium tert-butoxide (1039.0 mg, 9.26 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (86.4 mg, 0.14 mmol) andtris(dibenzylideneacetone)dipalladium(0) (63.6 mg, 0.06 mmol), whilecontinuing to purge with nitrogen. Nitrogen flow was discontinued andthe flask was sealed and heated at 90° C. for 8 h. The reaction wascooled and the solvent was removed by rotary evaporation. The resultingresidue was suspended in saturated aqueous sodium bicarbonate (10 mL)and extracted with chloroform (4×25 mL). The combined organic extractswere dried (Na₂SO₄), filtered, and concentrated by rotary evaporation toa thick dark mass. Purification by column chromatography, usingmethanol/chloroform (2:98, v/v) as the eluent, gave 0.54 g of thedesired compound as a light brown viscous liquid (69%).

7-(5-Ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane

To a solution of1-benzyl-7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (540 mg, 1.6mmol) in ethanol (25 mL) in a pressure bottle was added concentrated HCl(1 mL) and Pearlman's catalyst (Pd(OH)₂, 20% on carbon, 50 mg). Thesolution was shaken under 50 psi of hydrogen gas for 8 h. The catalystwas removed by filtration through Celite, and the filter cake was washedwith ethanol (20 mL). The solvent was removed by rotary evaporation, andthe residue was basified with saturated aqueous sodium bicarbonate to pH8-9. Solid sodium chloride (2 g) was added, and the mixture wasextracted with chloroform (4×20 mL). The combined chloroform extractswere dried (Na₂SO₄), filtered and concentrated by rotary evaporation toafford 360.7 mg of the desired compound as a light brown viscous liquid(91.1%).

1-Methyl-7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane

To a stirring solution of7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (360.4 mg, 1.4 mmol) in37% aqueous solution of formaldehyde (4 mL) was added 98% formic acid (2mL) under nitrogen. The reaction mixture was heated to reflux for 8 h.The reaction mixture was cooled to room temperature, then basified withsaturated aqueous sodium bicarbonate to pH 8-9 and extracted withchloroform (4×15 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered and concentrated by rotary evaporation to afford aviscous brown liquid. This was distilled using a Kugelrohr apparatus (2mm, 180° C.) to give a very light cream-colored syrup (340 mg, 89.3%).

Example 5

Sample 5 is 1-methyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane,which was prepared according to the following techniques:

3-Bromo-5-phenoxypyridine

Sodium hydride (1.35 g of 80% in mineral oil, 45.0 mmol) was added to astirred solution of phenol (4.26 g, 45.3 mmol) in DMF (30 mL) at 0° C.,under nitrogen. The mixture was stirred at room temperature for 3 h,treated with 3,5-dibromopyridine (4.0 g, 16.9 mmol) and heated at 100°C. for 48 h. The reaction mixture was cooled to room temperature, pouredinto a mixture of water (100 mL) and 5M sodium hydroxide (10 mL), andextracted with ether (3×60 mL). The combined ether extracts were dried(Na₂SO₄), filtered, and rotary evaporated to a pale yellow semi-solid(4.9 g). This was chromatographed on a silica gel (200 g) column withhexane/ethyl acetate/chloroform (8:1:1, v/v) as eluent to give 2.86 g(68% yield) of a colorless oil.

1-Benzyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane

1-Benzyl-1,7-diazaspiro[4.4]nonane (500.0 mg, 2.4 mmol) was dissolved indry toluene (15 mL) in a 50 mL round bottom flask equipped with amagnetic stirring bar. Nitrogen was bubbled through the solution in aslow stream. To the stirring solution was added3-bromo-5-phenoxypyridine (636.8 mg, 2.55 mmol), potassium tert-butoxide(1039.0 mg, 9.26 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(86.4 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (63.6mg, 0.06 mmol), while continuing to purge with nitrogen. Nitrogen flowwas discontinued and the flask was sealed and heated at 90° C. for 8 h.The reaction was cooled and the solvent was removed by rotaryevaporation. The resulting residue was suspended in saturated aqueoussodium bicarbonate (10 mL) and extracted with chloroform (4×25 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered, concentrated byrotary evaporation to a thick dark mass. This was purified by columnchromatography, using methanol/chloroform (2:98, v/v) as the eluent, toafford 0.70 g of the desired compound as a light brown viscous liquid(78.6%).

7-(5-Phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane

To a solution of1-benzyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (690 mg, 1.79mmol) in ethanol (25 mL) in a pressure bottle was added concentrated HCl(1 mL) and Pearlman's catalyst (Pd(OH)₂, 20% on carbon, 50 mg). Thesolution was shaken under 50 psi of hydrogen gas for 8 h. The catalystswas removed by filtration through Celite, and the filter cake was washedwith ethanol (20 mL). The solvent was removed by rotary evaporation, andthe residue was basified with saturated aqueous sodium bicarbonate to pH8-9. Solid sodium chloride (2 g) was added, and the solution wasextracted with chloroform (4×20 mL). The combined chloroform extractswere dried (Na₂SO₄), filtered and concentrated by rotary evaporation toafford 490 mg of the desired compound as a light brown viscous liquid(92.7%).

1-Methyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane

To a stirring solution of7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (420 mg, 1.42 mmol) in37% aqueous solution of formaldehyde (5 mL) was added 98% formic acid (3mL) under nitrogen. The reaction mixture was heated to reflux for 8 h.The reaction mixture was cooled to room temperature, then basified withsaturated aqueous sodium bicarbonate to pH 8-9 and extracted withchloroform (4×15 mL). The combined chloroform extracts were dried(Na₂SO₄), filtered and concentrated by rotary evaporation to afford athick brown viscous liquid. This was distilled using a Kugelrohrapparatus (2 mm, 180° C.) to give a very pale cream-colored syrup (400mg, 90.9%).

1-Methyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonanedihydrochloride

1-Methyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (200 mg, 0.65mmol) was dissolved in concentrated HCl (˜1 mL) and sonicated for 5 min.The excess acid and water were removed by repeated azeotropicevaporation with small portions of ethanol. A pale yellow solid wasobtained. The solid was dissolved in the minimum amount of absoluteethanol (˜1 mL), and then ether was added drop-wise until the solutionbecame opaque. Cooling in the refrigerator overnight producedcream-colored crystals, which were filtered, washed with ether and driedin a vacuum oven to yield 210 mg (85.4%) of pure dihydrochloride salt,m.p. 180-191° C.

Example 6

Sample 6 is1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]dihydrochloride,which was prepared according to the following techniques:

(3-oxolanyl)methyl methanesulfonate

To a stirring solution of (3-oxolanyl)methan-1-ol (25 g, 245 mmol) andtriethylamine (34.37 mL, 245 mmol) in dry dichloromethane (250 mL) at 0°C. under N₂ atmosphere was added dropwise methanesulfonyl chloride(18.94 mL, 245 mmol). The reaction mixture was stirred overnight afterwarming to room temperature, then a saturated solution of NaHCO₃ (100mL) was added and the mixture stirred for another 30 min. The biphasicmixture was separated and the organic layer was discarded. The aqueouslayer was extracted with dichloromethane (3×25 mL) and the combineddichloromethane extracts were dried (Na₂SO₄), filtered and concentratedby rotary evaporation to give 42.16 g of (3-oxolanyl)methylmethanesulfonate (99%) as a light brown liquid.

3-(Bromomethyl)oxolane

To a stirring solution of (3-oxolanyl)methyl methanesulfonate (42.16 g,239.5 mmol) in dry acetone (600 mL) was added lithium bromide (101.7 g,1198 mmol). The reaction mixture was heated to reflux for 3 h, then itwas cooled and the solvent removed by rotary evaporation. The residuewas dissolved in water (200 mL) and extracted with dichloromethane(2×100 mL). The combined extracts were dried (Na₂SO₄), filtered andconcentrated by rotary evaporation to afford a light brown liquid. Itwas distilled at 70° C. and 1 mm of pressure to give 33.00 g (86.77%) of3-(bromomethyl)oxolane as a colorless liquid.

Methyl 3-aza-4,4-diphenyl-but-3-enoate

To a stirring solution of methyl glycine ester hydrochloride (17.49 g,139 mmol) in dry dichloromethane (150 mL) under N₂ at room temperaturewas added diphenylimine (25.00 g, 137 mmol) in one portion. The reactionmixture was stirred for 24 h, during which time ammonium chlorideprecipitated. Water (20 mL) was added and the layers were separated. Theorganic layer was washed with saturated Na₂CO₃ solution (2×20 mL) andbrine (20 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated by rotary evaporation to give 35 g of a thick light brownsyrup (99% pure) in ˜100% yield. This was taken on to the next reactionwithout further purification.

Methyl 3-(3-oxolanyl)-2-aminopropanoate

To a stirring solution of methyl 3-aza-4,4-diphenyl-but-3-enoate (23.00g, 90 mmol) under N₂ in dry DMF (25 mL) and toluene (25 mL) was addedpotassium tert-butoxide (10.20 g, 90 mmol) in one portion. The reactionmixture was stirred for 15 min; it changed color from yellow to darkreddish-brown. Then, a solution of 3-(bromomethyl)oxolane (15 g, 90mmol) in DMF (20 mL) and dry toluene (20 mL) was added via cannula overa period of 30 min. The reaction mixture was stirred for an additional16 h at ambient temperature. Then, 1N HCl (100 mL) was added to thereaction mixture and it was stirred for another 30 min. The mixture wasextracted with ethyl acetate (3×50 mL). The aqueous layer was basifiedwith solid K₂CO₃ to pH 8-9, then saturated with solid NaCl and extractedwith ethyl acetate (4×50 mL). The combined ethyl acetate extracts weredried (K₂CO₃), filtered and concentrated by rotary evaporation to givemethyl 3-(3-oxolanyl)-2-aminopropanoate (10 g, 59.37%) as a brownliquid.

Ethyl 1-azabicyclo[2.2.1]heptane-2-carboxylate

Methyl 3-(3-oxolanyl)-2-aminopropanoate (6.00 g, 3.46 mmol) was placedin a sealed pressure tube, then 48% aqueous HBr (20 mL) was added andthe solution was saturated with HBr gas. The tube was sealed carefullyand heated at 110°-120° C. for 8 h. The reaction was then cooled and thecontents transferred to a 250 mL round bottom flask with 20 mL of water.The excess acid was removed by rotary evaporation to give a semi solidbrown mass. Then 30% aqueous ammonium hydroxide (150 mL) was added at 0°C. and the mixture was heated at gentle reflux for 4 h. The solvent wasremoved by rotary evaporation to give a brown solid, which then wasdissolved in absolute ethanol (50 mL). Concentrated H₂SO₄ (10 mL) wasadded and the solution was refluxed for 8 h. The contents were cooled inan ice bath, and then basified with concentrated NaHCO₃ solution to pH8-9 and extracted with chloroform (4×40 mL). The combined chloroformextracts were dried (K₂CO₃), filtered and concentrated to give abrown-black liquid which was distilled using a Kugelrohr apparatus (1mm, 140° C.) to afford a colorless liquid (4 g, 68.25%) as a mixture ofthe exo and endo isomers of ethyl1-azabicyclo[2.2.1]heptane-2-carboxylate.

Ethyl 1-aza-2-(nitroethyl)bicyclo[2.2.1]heptane-2-carboxylate

Lithium diisopropylamide (LDA) was prepared at 0° C. fromdiisopropylamine (2.078 g, 20.53 mmol) and n-butyllithium (8.21 mL,20.53 mmol) in dry THF (20 mL) under an N₂ atmosphere. To a stirringsolution of a mixture of the exo and endo isomers of ethyl1-azabicyclo[2.2.1]heptane-2-carboxylate (2.67 g, 15.79 mmol) in dry THF(35 mL) at −78° C. under N₂ atmosphere was added via cannula the LDAsolution over a period of 15 min. The reaction mixture was stirred foran additional 40 minutes. Then a solution of nitroethylene (1.45 g,20.53 mmol) in dry THF (20 mL) was added dropwise via cannula to thereaction mixture over a period of 15 min. After stirring for 2 h at −78°C., the reaction was quenched by adding a saturated solution of ammoniumchloride (20 mL). It was extracted with ethyl acetate (5×25 mL), dried(Na₂SO₄), filtered and concentrated by rotary evaporation to give 3.82 gof the desired product (86% pure) as a light brown liquid, which wastaken on to the next step without further purification.

2′H-spiro[azabicyclo[2.2.1]heptane-2,3′-pyrrolidin]-2′-one

Ethyl 1-aza-2-(nitroethyl)bicyclo[2.2.1]heptane-2-carboxylate (3.82 g,86% pure, 15.78 mmol) was dissolved in ethanol (50 mL) in ahydrogenolysis bottle. A catalytic amount of Raney nickel was added andthe mixture was subjected to hydrogenolysis at 50 psi on a Parrapparatus for 16 h. The catalyst was removed by filtration through acelite plug and washed with ethanol (20 mL). A catalytic amount (5 mg)of p-toluenesulfonic acid was added and the reaction mixture wasrefluxed for 12 h. The solvent was removed by rotary evaporation toafford a light brown solid. This was dissolved in conc. NaHCO₃ solution(10 mL), saturated with NaCl and extracted with chloroform (4×40 mL).The combined chloroform extracts were dried (K₂CO₃), filtered andconcentrated by rotary evaporation to give a light brown solid. It waspurified by column chromatography, using MeOH: CHCl₃:NH₄OH (9:1:0.01,v/v) as the eluent, to afford 1.96 g (75%) of2′H-spiro[azabicyclo[2.2.1]heptane-2,3′-pyrrolidin]-2′-one as acream-colored solid (m.p. 98° C.).

Spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]

To a solution of2′H-spiro[azabicyclo[2.2.1]heptane-2,3′-pyrrolidin]-2′-one (1.00 g, 6.02mmol) in dry THF (20 mL) at 0° C. under N₂ atmosphere was added lithiumaluminum hydride (647 mg, 17.7 mmol) and the mixture was refluxed for 24h. The reaction mixture was cooled in ice bath and then ether (20 mL)was added. Excess hydride was quenched by the dropwise addition of 5 Msolution of NaOH. The resulting solid aluminate salts were removed byfiltration through a celite plug. The filtrate was dried (Na₂SO₄),filtered and concentrated by rotary evaporation to yield 800 mg ofspiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] as a colorless liquid(87.43%).

1′-(3-Pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]dihydrochloride

A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (300 mg,1.98 mmol), 3-bromopyridine (344 mg, 2.18 mmol),tris(dibenzylideneacetone)dipalladium(0) (54.57 mg, 0.0654 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (74.22 mg, 0.131 mmol)and potassium tert-butoxide (668.8 mg, 5.96 mmol) in dry toluene (20 mL)was heated in a sealed tube flushed with argon gas at 90° C. for 8 h.The reaction was cooled to 0° C. and the contents transferred to a 100mL round bottom flask. The solvent was removed by rotary evaporation andthe residue was dissolved in a saturated solution of NaHCO₃ (10 mL) andextracted with chloroform (4×15 mL). The combined chloroform extractswere dried (K₂CO₃), filtered and concentrated by rotary evaporation togive a dark colored syrup. This was purified by column chromatography,using MeOH:CHCl₃:NH₄OH (8:2:0.01, v/v) as the eluent, to afford 350 mg(79.0%) of1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] as alight brown syrup. A portion of the free base (200 mg) was converted toa hydrochloride salt, which was crystallized from isopropanol andethanol to yield 200 mg (76%) of a light brown solid, (m.p. 232°-236°C.).

Example 7

Sample 7 is1′-(5-ethoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine],which was prepared according to the following techniques:

1′-(5-Ethoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]

A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (50 mg,0.3 mmol) tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.009 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (12 mg, 0.018 mmol),potassium tert-butoxide (147 mg, 1.2 mmol), and 5-bromo-3-ethoxypyridine(73 mg, 0.36 mmol) in dry toluene (5 mL) was placed in a sealed tubeunder argon and heated at 160° C. for 17 h. The reaction was cooled to0° C. and the contents transferred to a 100 mL round bottom flask. Thesolvent was removed by rotary evaporation and the residue was dissolvedin a saturated solution of NaHCO₃ (10 mL) and extracted with chloroform(4×15 mL). The combined chloroform extracts were dried (K₂CO₃), filteredand concentrated by rotary evaporation to give a dark colored syrup.This was purified by column chromatography, using MeOH:C Cl₃H:NH₄OH(8:2:0.01, v/v) as the eluent, to give 28 mg (27%) of1′-(5-ethoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]as a viscous brown oil.

Example 8

Sample 8 is1′-(5-phenoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine],which was prepared according to the following techniques:

1′-(5-Phenoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]

A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (50 mg,0.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.009 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (12 mg, 0.018 mmol),potassium tert-butoxide (147 mg, 1.3 mmol), and5-bromo-3-phenoxypyridine (90 mg, 0.36 mmol) in dry toluene (5 mL) washeated in a sealed tube under argon at 160° C. for 17 h. The reactionwas cooled to 0° C. and the contents transferred to a 100 mL roundbottom flask. The solvent was removed by rotary evaporation and theresidue was dissolved in a saturated solution of NaHCO₃ (10 mL) andextracted with chloroform (4×15 mL). The combined chloroform extractswere dried (K₂CO₃), filtered and concentrated by rotary evaporation togive a dark colored syrup. This was purified by column chromatography,using MeOH:CHCl₃:NH₄OH (8:2:0.01, v/v) as the eluent, to afford 55.8 mgof1′-(5-phenoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine](52%) as a viscous tan oil.

Example 9

Sample 9 is1′-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine],which was prepared according to the following techniques:

1′-(5-Pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]

A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (100 mg,0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.0018mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (24 mg, 0.0036mmol), potassium tert-butoxide (300 mg, 2.6 mmol), and 5-bromopyrimidine(114 mg, 0.7 mmol) in dry toluene (10 mL) was placed in a sealed tubeunder argon and heated at 125° C. for 17 h. The reaction was cooled to0° C. and the contents transferred to a 100 mL round bottom flask. Thesolvent was removed by rotary evaporation and the residue was dissolvedin a saturated solution of NaHCO₃ (10 mL) and extracted with chloroform(4×15 mL). The combined chloroform extracts were dried (K₂CO₃), filteredand concentrated by rotary evaporation to give a dark colored syrup.This was purified by column chromatography, using MeOH:CHCl₃:NH₄OH(8:2:0.01, v/v) as the eluent, to afford 49.0 mg of1′-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine](32%) as a viscous brown oil.

Example 10

Sample 10 is1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine], whichwas prepared according to the following techniques:

Ethyl quinuclidine-2-carboxylate

The ethyl quinuclidine-2-carboxylate for this synthesis was preparedaccording to the method described by Ricciardi and Doukas (Heterocycles24:971 (1986)). We have also prepared ethyl quinuclidine-2-carboxylateusing chemistry analogous to that used for the synthesis of ethyl1-azabicyclo[2.2.1]heptane-2-carboxylate, but using 4-(bromomethyl)oxanein place of 3-(bromomethyl)oxolane.

Ethyl 2-(2-nitroethyl)quinuclidine-2-carboxylate

Lithium diisopropylamide was prepared at 0° C. from lithiumdiisopropylamine (193.53 mg, 1.91 mmol) and n-butyllithium (0.764 mL,1.91 mmol) under N₂. It was added via cannula to a stirring solution ofethyl quinuclidine-2-carboxylate (320 mg, 1.74 mmol) in dry THF (10 mL)at −78° C. After 1 h, a solution of nitroethylene (140.41 mg, 1.91 mmol)in THF (5 mL) was added dropwise to the reaction mixture. After stirringfor 2 h at −78° C., the reaction was quenched by adding a saturatedsolution of ammonium chloride (20 mL). It was extracted with ethylacetate (5×25 mL), dried (Na₂SO₄), filtered and concentrated by rotaryevaporation to give 325 mg (70% pure) ethyl2-(2-nitroethyl)quinuclidine-2-carboxylate as a light brown liquid,which was taken on to the next step without further purification.

2′H-spiro[azabicyclo[2.2.2]octane-2,3′-pyrrolidin]-2′-one

A solution of ethyl 2-(2-nitroethyl)quinuclidine-2-carboxylate (320 mg,) in ethanol (10 mL) was subjected to hydrogenolysis at 50 psi on a Parrapparatus for 16 h using Raney nickel as a catalyst. The catalyst wasremoved by filtration through a celite plug and washed with ethanol (20mL). A catalytic amount (5 mg) of p-toluenesulfonic acid was added andthe reaction mixture was refluxed for 12 h. The solvent was removed byrotary evaporation to afford a light brown solid. This was dissolved inconc. NaHCO₃ solution (10 mL), saturated with NaCl and extracted withchloroform (4×40 mL). The combined chloroform extracts were dried(K₂CO₃), filtered and concentrated by rotary evaporation to give a lightbrown solid. It was purified by chromatography, using MeOH:CHCl₃:NH₄OH(8:2:0.01, v/v) as the eluent, to give 120 mg (38.2%) of desiredcompound as light cream-colored solid (m.p. 103°-105° C.).

Spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]

To a solution of2′H-spiro[azabicyclo[2.2.2]octane-2,3′-pyrrolidin]-2′-one (100 mg, 0.55mmol) in dry THF (10 mL) at 0° C. under N₂ atmosphere was added lithiumaluminum hydride (74 mg, 1.94 mmol) and the mixture was refluxed for 24h. The reaction mixture was cooled in ice bath and then ether (20 mL)was added. Excess hydride was quenched by the dropwise addition of 5 Msolution of NaOH. The resulting solid aluminate salts were removed byfiltration through a celite plug. The filtrate was dried (Na₂SO₄),filtered and concentrated by rotary evaporation to yield 83 mg ofspiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine] as a colorless liquid(90%).

1′-(3-Pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine]

A stirring solution of spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine](80 mg, 0.48 mmol), tris(dibenzylidineacetone)dipalladium(0) (26.47 mg,0.024 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (30 mg,0.048 mmol) and potassium tert-butoxide (215 mg, 1.92 mmol) in drytoluene (15 mL) was placed in a sealed tube under argon and heated at90° C. for 16 h. The reaction was cooled to 0° C. and the contentstransferred to a 100 mL round bottom flask. The solvent was removed byrotary evaporation and the residue was dissolved in a saturated solutionof NaHCO₃ (10 mL) and extracted with chloroform (4×15 mL). The combinedchloroform extracts were dried (K₂CO₃), filtered and concentrated byrotary evaporation to give a dark colored syrup. This was purified bycolumn chromatography, using MeOH:CHCl₃:NH₄OH (8:2:0.01, v/v) as theeluent, to give 102 mg (85.7%) of1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine] as alight brown syrup.

Example 11

Sample 11 is1′-(3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine],which was prepared according to the following techniques:

Ethyl 2-(2H,3H,5H-4-oxinyl)-2-nitroacetate

A 2 M solution of titanium tetrachloride in THF was made by slowaddition of the titanium tetrachloride (7.59 g, 40 mmol) to dry THF (20mL) at 0° C. under a nitrogen atmosphere. Ethyl nitroacetate (2.66 g, 20mmol) was then added to the stirring solution, and the mixture wasstirred for 5 min. Next, tetrahydro-4-H-pyran-4-one (2.00 g, 20 mmol)was added in one portion. Then, a 1.0 M solution of N-methyl morpholinein THF (8.09 g, 80 mmol) was added dropwise over a period of 2 h at 0°C. The mixture was then allowed to warm to room temperature and wasstirred for 18 h. It was then poured into water (20 mL) and extractedwith ethyl acetate (5×40 mL). The combined extracts were dried overNa₂SO₄, filtered and concentrated by rotary evaporation. The thick brownsyrup was purified by column chromatography, using ethyl acetate:hexane(1:9, v/v) as eluent, to afford 3.00 g of pure compound as a light-brownsyrup (70%).

Ethyl 2-(4-oxanyl)-2-aminoacetate

Raney nickel (˜2 g) was added to a solution of ethyl2-(2H,3H,5H-4-oxinyl)-2-nitroacetate (2.50 g, 11.62 mmol) in ethanol (50mL) and conc. HCl (1 mL). The mixture was subjected to hydrogenolysis at50 psi on a Parr apparatus for 18 h. The catalyst was removed by carefulfiltration through a celite plug. The solvent was removed by rotaryevaporation. The residue was basified with saturated aqueous NaHCO₃ topH 8-9, then saturated with NaCl and extracted with chloroform (4×25mL). The combined extracts were dried over K₂CO₃, filtered andconcentrated to yield 2.40 g (˜100%) of desired compound as a tanliquid.

1-azabicyclo[2.2.1]heptane-7-carboxylic Acid Hydrochloride

Ethyl 2-(oxanyl)-2-aminoacetate (1.50 g, 8.02 mmol) was dissolved in 48%HBr (10 mL) in a pressure tube and saturated with HBr gas. The tube wassealed carefully and heated for 12 h at 120′-130° C. The reaction wascooled to room temperature, transferred to a 250 mL round bottom flask,and the acid was removed by rotary evaporation. The dark colored residuewas dissolved in 30% ammonia solution (50 mL). This mixture was stirredfor 5 h at room temperature, until cyclization to the desired acid wascomplete. The ammonia solution was removed by rotary evaporation toafford a light brown solid, which was redissolved in 5 mL of water andpurified on an ion exchange resin using water as the eluent and ammonia(30% aq.). Ammoniacal fractions containing the desired acid werecombined and concentrated to afford pure acid, which was converted to anHCl salt and crystallized from isopropanol and diethyl ether to give1.21 g (85%) of a cream-colored solid (m.p. 232° turns brown, melts at253°-254° C.).

Ethyl 1-azabicyclo[2.2.1]heptane-7-carboxylate

A solution of 1-azabicyclo[2.2.1]heptane-7-carboxylic acid hydrochloride(1.20 g, 6.76 mmol) in absolute ethanol (10 mL) and concentratedsulfuric acid (2 mL) was refluxed for 8 h. The reaction mixture wascooled and then basified with saturated aqueous NaHCO₃ to pH 8-9. Thesolution was saturated with solid NaCl and extracted with chloroform(4×20 mL). The combined chloroform extracts were dried over Na₂SO₄,filtered and concentrated by rotary evaporation to give a light brownliquid. This was purified by Kugelrohr distillation at 120° C. and 2.5mm pressure to afford 1.00 g (90%) as a colorless liquid.

Ethyl 1-aza-7-(2-nitroethyl)bicyclo[2.2.1]heptane-7-carboxylate

Lithium diisopropylamide was prepared by the addition of n-butyllithium(1.70 mL, 6.26 mmol) to diisopropylamine (431.1 mg, 6.26 mmol) in dryTHF (5 mL) at 0° under a N₂ atmosphere. The reaction was stirred at roomtemperature for 15 min and then transferred via cannula to a stirringsolution of ethyl 1-azabicyclo[2.2.1]heptane-7-carboxylate (600 mg, 3.55mmol) in THF (20 mL) at −78° C. under a N₂ atmosphere. The reactionmixture was stirred for 30 min at −78° C., then a solution ofnitroethylene (285.3 mg, 3.91 mmol) in THF (10 mL) was added via cannulaand the reaction was stirred for additional 2 h at −78° C. Then thereaction was quenched with saturated NH₄Cl solution (10 mL). Thereaction mixture was allowed to warm to room temperature and then wasextracted with ethyl acetate (4×20 mL). The combined fractions weredried (K₂CO₃), filtered and concentrated by rotary evaporation to give650 mg of a light-brown liquid. It was purified by columnchromatography, using ethyl acetate:dichloromethane (8:2, v/v), to give600 mg (85%) of tan liquid.

2′H-Spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidin]-2′-one

Ethyl 1-aza-7-(2-nitroethyl)bicyclo[2.2.1]heptane-7-carboxylate (550 mg,2.27 mmol) was dissolved in ethanol (25 mL) and subjected tohydrogenolysis at 50 psi for 18 h, using Raney nickel as a catalyst. Thecatalyst was removed by filtration through a celite plug. The solventwas removed by rotary evaporation. The resultant residue was dissolvedin toluene (50 mL) and a catalytic amount of p-toluenesulfonic acid (10mg) was added. The solution was refluxed for 12 h and then the solventwas removed by rotary evaporation. The residue was added to saturatedNaHCO₃ (10 mL) solution and extracted with chloroform (5×15 mL). Thecombined chloroform extracts were dried (K₂CO₃), filtered, andconcentrated. The residue was purified by column chromatography, usingCHCl₃:MeOH:NH₄OH (9:1:0.01, v/v) as the eluent, to afford 320 mg (85%)of pure compound as a cream-colored thick syrup.

2′H-Spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]

To a stirring solution of2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidin]-2′-one (300 mg,1.80 mmol) in dry THF (30 mL) at 0° under N₂ was added LiAlH₄ (274.33mg, 7.22 mmol). The ice bath was removed and the reaction mixture wasrefluxed for 24 h. The reaction mixture was cooled to 0° C., diethylether (20 mL) was added and 5M NaOH was added dropwise with constantstirring until all unreacted LiAlH₄ solidified. The reaction mixture wasfiltered through celite and then the filtrate was dried (K₂CO₃),filtered and concentrated by rotary evaporation to yield 250 mg (70%) ofa colorless syrup.

1′-(3-Pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine]

2′H-Spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine] (100 mg, 0.66mmol), tris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.020 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (45 mg, 0.040 mmol),potassium tert-butoxide (369 mg, 3.3 mmol) and 3-bromopyridine (114 mg,0.72 mmol) and dry toluene (10 mL) were placed in a pressure tube whichwas flushed with argon. The tube was carefully sealed and heated for 8 hat 90° C. The reaction mixture was cooled, transferred to a round bottomflask and the solvent removed by rotary evaporation. The residue waspoured into saturated NaHCO₃ solution (5 mL) and extracted withchloroform (4×15 mL). The combined chloroform extracts were dried overK₂CO₃, filtered and concentrated by rotary evaporation. The residue waspurified by column chromatography, using CHCl₃:MeOH:NH₄OH (8:2:0.01,v/v) as eluent, to afford 130 mg (86.7%) of a light brown syrup. Theproduct turns dark brown on exposure to light and air.

Examples 12 and 13

Samples 12 and 13 are (+) and (−)7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane respectively, which wereprepared according to the following techniques:

Diastereomeric 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane S-proline amides

Triethylamine (6.0 mL, 43 mmol) and diphenyl chlorophosphate (4.0 mL, 19mmol) were added, in that order, to a stirred suspension ofN-(tert-butoxycarbonyl)-S-proline (4.67 g, 21.7 mmol) in dichloromethane(100 mL) under a nitrogen atmosphere. After stirring for 1.5 h atambient temperature, the reaction mixture was treated with a solution of7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane (4.40 g, 21.6 mmol) indichloromethane (10 mL). The mixture was stirred 3 days at ambienttemperature. Sodium hydroxide solution (30 mL of 5 M) was then added.After stirring an additional hour, the mixture was poured into aseparatory funnel with chloroform (30 mL) and water (30 mL). The mixturewas shaken vigorously, and the layers were separated. The organic layerand a 30 mL chloroform extract of the aqueous layer were combined, dried(MgSO₄) and concentrated by rotrary evaporation. The residue (7.2 g) wasdissolved in dichloromethane (100 mL) and combined with trifluroaceticacid (50 mL). The mixture was stirred at ambient temperature for 1 h.The volatiles were evaporated, first by rotary evaporation and then onthe vacuum pump. The residue was purified by preparative HLPC, using 10%acetonitrile, 0.1% trifluoroacetic acid in water as eluent. Selectedfractions were combined and concentrated, leaving 3.13 g (79% yield) ofthe diastereomer which elutes at 11.4 min and 2.90 g (74% yield) of thediastereomer that elutes at 13.2 min, both as white foams (presumablymono trifluoroacetate salts).

(+) and (−) 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane

Each of the two diastereomeric S-proline amides was dissolved indichloromethane (50 mL) and triethylamine (2-3 mL), and then combinedwith phenylisothiocyanate (1.73 g, 12.8 mmol for the earlier elutingdiastereomer and 1.57 g, 11.6 mmol for the later eluting diastereomer).The two reactions were stirred at ambient temperature for 16 h, at whichpoint thin layer chromatography indicated that the reactions werecomplete. The mixtures were concentrated by rotary evaporation, and eachof the residues was taken up in dichloromethane (10 mL) and treated withtrifluoroacetic acid (10 mL). These reactions were held at 50° C. for 16h and concentrated to dryness. Column chromatography on silica gel with80:20:2 chlorform/methanol/ammonia gave 620 mg (derived from the earliereluting diastereomer, 40.5% yield) and 720 mg (derived from the latereluting diastereomer, 50.7% yield), as light brown oils. Chiral HPLCanalysis was perormed on a Chiralcel OD® column, using 7:3hexane/ethanol. The isomer derived from the earlier eluting diastereomerhad the longer retention time on the chiral column (10.9 min); thatderived from the later eluting isomer exhibited a retention time of 8.7min on the chiral column. The samples were enantiomerically pure withinthe limits of detection (˜2%).

Having hereby disclosed the subject matter of the present invention, itshould be apparent that many modifications, substitutions, andvariations of the present invention are possible in light thereof. It isto be understood that the present invention can be practiced other thanas specifically described. Such modifications, substitutions andvariations are intended to be within the scope of the presentapplication.

1. A compound having the following formula:

or a pharmaceutically acceptable salt thereof, wherein Q^(I) is(CH₂)_(u), Q^(II) is (CH₂)_(v), Q^(III) is (CH₂)_(w), Q^(IV)is(CH₂)_(x), Q^(V) is(CH₂)_(y), and Q^(VI) is (CH₂)_(z), where u, v, w,x, y, and z are individually 0, 1, 2, 3, or 4, and the values of u, v,w, x, y, and z are selected such that the bridged diazaspirocyclic ringis a spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine]ring,spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine] ring, orspiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine] ring; Cy is a sixmembered ring of the formula:

where each of X, X′, X″, X′″, and X″″ is individually (i) nitrogen, (ii)nitrogen bonded to oxygen, or (iii) carbon bonded to H, phenoxy, oralkoxy, wherein no more than three of X, X′, X″, X′″, and X″″ arenitrogen or nitrogen bonded to oxygen, or Cy is a five 5-memberedheteroaromatic ring of the formula:

where Y and Y″ are individually (i) nitrogen; (ii) nitrogen bonded to H,phenoxy, or alkoxy; (iii) oxygen; (iv) sulfur; or (v) carbon bonded toH, phenoxy, or alkoxy, and Y′ and Y′″ are nitrogen or carbon bonded toH, phenoxy, or alkoxy; and wherein the dashed lines indicate that thebonds between Y and Y′ and between Y′ and Y″ can be either single ordouble bonds, with the proviso that when the bond between Y and Y′ is asingle bond, the bond between Y′ and Y″ must be a double bond and whenthe bond between Y and Y′ is a double bond, the bond between Y′ and Y″must be a single bond, where Y or Y″ is oxygen or sulfur, only one of Yand Y″ is either oxygen or sulfur, and at least one of Y, Y′, Y″, andY′″ must be oxygen, sulfur, nitrogen, or nitrogen bonded to H, phenoxy,or alkoxy.
 2. The compound of claim 1, wherein only one or two of X, X′,X″, X′″, and X″″ are nitrogen or nitrogen bonded to oxygen.
 3. Thecompound of claim 1, wherein not more than one of X, X′, X″, X′″, andX″″ are nitrogen bonded to oxygen.
 4. The compound of claim 1, whereinX′″ is nitrogen or nitrogen bonded to oxygen.
 5. The compound of claim1, wherein both X′ and X′41 are nitrogen.
 6. The compound of claim 1,wherein X, X″, and X″″ are carbon bonded to H, phenoxy, or alkoxy. 7.The compound of claim 6, wherein X, X″, and X″″ are each carbon bondedto hydrogen.
 8. The compound of claim 1, wherein X′″ is carbon bonded toH, phenoxy, or alkoxy and X and X′ are both nitrogen; or X′ is carbonbonded to H, phenoxy, or alkoxy and X and X′″ are both nitrogen.
 9. Thecompound of claim 1, wherein no more than three of Y, Y′, Y″, and Y′″are oxygen, sulfur, nitrogen, or nitrogen bonded to H, phenoxy, oralkoxy.
 10. The compound of claim 1, wherein between one and three of Y,Y′, Y″, and Y′″ are nitrogen.
 11. A compound selected from the groupconsisting of:1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-ethoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-cyclopentyloxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-phenoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-isoxazolyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-isothiazolyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-(1,2,4-oxadiazol)yl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(2-(1,3,4-oxadiazol)yl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(2-pyrazinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(3-pyridazinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(5-ethynyl-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(6-chloro-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(6-methoxy-3-pyridazinyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine];1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-methoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-cyclopentyloxy-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-phenoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-(4-hydroxyphenoxy)-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-ethynyl-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(6-chloro-3-pyridyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-pyrimidinyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(2-pyrazinyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(3-pyridazinyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(6-methoxy-3-pyridazinyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-isoxazolyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-isothiazolyl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(5-(1,2,4-oxadiazol)yl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(2-(1,3,4-oxadiazol)yl)-spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine];1′-(3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(5-methoxy-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(5-cyclopentyloxy-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(5-phenoxy-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(5-(4-hydroxyphenoxy)-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(6-chloro-3-pyridyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(5-pyrimidinyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(2-pyrazinyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(3-pyridazinyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(6-methoxy-3-pyridazinyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(5-isoxazolyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(5-isothiazolyl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];1′-(5-(1,2,4-oxadiazol)yl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine];and1′-(2-(1,3,4-oxadiazol)yl)-2′H-spiro[1-azabicyclo[2.2.1]heptane-7,3′-pyrrolidine],or a pharmaceutically acceptable salt thereof.